KR20230170654A - Methyl-substituted pyridine and pyridazine compounds, derivatives thereof, and methods of using the same - Google Patents

Abstract

The present invention provides methyl-substituted pyridine and pyridazine compounds, derivatives thereof, and methods of using them. The compounds are useful as pharmacological agents for treating a variety of conditions, including various pain conditions, itching, and cough.

Description

Methyl-substituted pyridine and pyridazine compounds, derivatives thereof, and methods of using the same

This application generally relates to methyl-substituted pyridine and pyridazine compounds, their derivatives, and the use of such compounds as pharmacological agents.

Millions of people suffer from conditions associated with pain, itching and/or coughing. In many cases, the drugs used to treat these conditions either fail to provide relief or produce unacceptable side effects. Therefore, existing treatments are inadequate for many patients suffering from a variety of conditions.

The present invention provides compounds useful for the treatment of conditions associated with abnormal activity of voltage-gated Na _V 1.8 sodium channels, such as pain, itching and cough.

A. First set of compounds

In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.

here:

R ₁ is an optionally substituted 5 or 6 ring-membered ring comprising -CN, -CF ₃ , an aryl or heteroaryl ring, wherein the 5 or 6 ring-membered ring optionally contains one or more N or S in the ring; , Substitution on the 5 or 6 ring member ring is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring has 5 or is selected from fused heterocyclyl with 6 members, heteroaryl with 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₃ is halogen, alkyl or alkoxy;

R ₄ is halogen, alkyl or H;

R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring having 5 or 6 members. a fused heterocyclyl, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;

X is CH or N;

Z is CH or N,

However, both X and Z cannot be CH.

R ₂ may be -CH ₃ , -CD ₃ , or -CT ₃ where D is deuterium and T is tritium.

R ₃ may be -CH ₃ , -CD ₃ , or -CT ₃ where D is deuterium and T is tritium.

The moiety at R ₅ may be substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl or halogen.

Compounds of formula (I) may have the sulfoximine group in the R stereochemical configuration, the S stereochemical configuration, or a mixture of R and S stereochemical configurations.

In another aspect, the invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof.

here:

Each of J ₁ , J ₂ , J ₄ , and J ₅ is independently N, NO, or CR ₆ ;

J ₃ is N, NO, or CR ₇ ;

X is CH or N;

Y is NR ₈ or O;

Z is CH, N or N-O,

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

Each occurrence of R ₆ is independently H, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, CD ₃ or CT ₃ ;

R ₇ is H, halogen, -CD ₃ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, -CF ₃ , -OCF ₃ , each ring has 5 or heterocyclyl having 6 members, heteroaryl having 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, each ring having 5 or 6 members, O-aryl, each O-heteroaryl, O-cycloalkyl, O-cycloheteroalkyl, wherein the ring has 5 or 6 members, each of which is optionally substituted as valence permits;

R ₈ is H, C _1-3 alkyl, or C _3-5 cycloalkyl, acyl,

step,

X and Z cannot both be CH;

Two or less of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO.

R ₂ may be -CH ₃ , -CD ₃ , or -CT ₃ where D is deuterium and T is tritium.

Compounds of formula (II) may have the sulfoximine group in the R stereochemical configuration, the S stereochemical configuration, or a mixture of R and S stereochemical configurations.

In another aspect, the invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof.

here:

Each of J ₁ , J ₂ , J ₄ , and J ₅ is independently N, NO, or CR ₆ ;

J ₃ is N, NO, or CR ₇ ;

Each W ₁ , W ₂ , W ₃ , W ₄ , and W ₅ is independently N, CH, or CR ₉ ;

X is CH or N;

Z is CH, N or N-O,

Each occurrence of R ₆ is independently -H, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, CD ₃ or CT ₃ ;

R ₇ is -H, halogen, -CD ₃ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, -CF ₃ , -OCF ₃ , each ring Carbocyclyl with 3 to 6 members, heterocyclyl with each ring having 5 or 6 members, heteroaryl with 5 or 6 ring members, saturated hetero, with each ring having 3 to 6 members. Cycryl, or partially unsaturated heterocyclyl, O-aryl, each ring having 5 or 6 members, O-heteroaryl, each ring having 5 or 6 members, O-cycloalkyl, O-cyclohetero alkyl, each of which is optionally substituted where valency permits,

R ₉ in each case is independently -C(O)NR ₁₀ R ₁₁ , -S(O) ₂ C _1-6 alkyl, -S(O)(NH)C _1-6 alkyl, C _1-3 alkyl, or C _3-5 cycloalkyl;

Each R ₁₀ and R ₁₁ is independently selected from -H and C _1-5 alkyl, or R ₁₀ and R ₁₁ together with the nitrogen atom to which they are attached form a heterocyclyl having 3-6 members. and wherein each C _1-5 alkyl and heterocyclyl are optionally substituted if valency permits,

step,

Up to two of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO;

At most two of W ₁ , W ₂ , W ₃ , W ₄ and W ₅ are N;

Three or fewer of W ₁ , W ₂ , W ₃ , W ₄ and W ₅ are CR ₉ ;

X and Z cannot both be CH.

In another aspect, the invention provides compounds of formula (IV).

here:

Y is N or CR ₁₃ ;

A and B are independently aryl, heteroaryl, or a 3-6 membered ring containing one or more heteroatoms independently selected from O, S, and N; where A is unsubstituted or:

H, halo, C1-C6-alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, SR', -CH ₂ -cycloalkyl, -CF ₂ - Cycloalkyl, -CH(CH ₃ )-cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH(-CH ₃ )-aryl, C(=O)-alkyl, -C(=O)cyclo Alkyl, -C(=O)-NH-alkyl, -C(=O)NH ₂ , hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR'R"-NHSOR', -NHC(=O)-alkyl -NH(C=O)NR'R", SO ₂ R', trifluoromethyl, bromo, chloro, fluoro, cyclopropylmethyl, sulfonylmethyl, 3-6 membered cycloalkyl; is substituted with one or more substituents selected from 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl is independently selected from O, S, and N. contains at least one heteroatom;

R ₁₂ , R ₁₃ and R ₁₄ are individually selected from H, CF ₃ , halo, C1-C6-alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH ₂ -cycloalkyl, -CF ₂ -cycloalkyl, -CH(CH ₃ )-cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH(-CH ₃ )-aryl, C(=O )-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH ₂ , hydroxy, -COOH (and esters thereof), alkylsulfonyl, aryl sulphenyl Ponyl, sulfonamide, amino, NR'R" -NHSO ₂ R1, -NHC(=O)-alkyl -NH(C=O)NR'R", spirocyclyl, morpholinyl, pyrrolidinyl, piperidi selected from nyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein the 5 or 6 ring member ring optionally contains one or more N or S within the ring, and wherein substitution on the 5 or 6 ring member ring Silver halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, -C(=O)-NH-alkyl, -C(=O)NH ₂ cyano, CF ₃ , CHF ₂ , OCH ₃ , OCF ₃ , fused heterocyclyl with each ring having 5 or 6 members, heteroaryl with 5 or 6 ring members, saturated heterocyclyl or partially unsaturated heterocyclyl. and each of these is optionally substituted if valency permits;

Substituents R' and R" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. , or from CD ₃ can be selected

In selected embodiments, A is CH ₂ CF ₃ or am.

In another aspect, the invention provides compounds of formula (V).

here

A and B are as described for formula (IV);

R ₂ is as described for formula (II);

R ₁₃ and R ₁₄ are as described in formula (IV);

X is CH or N;

Y is NR ₈ or O;

Z is CH, N or N-O.

B. Second set of compounds

In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.

here:

R ₁ is -CN or -CF ₃ ;

R ₃ is halogen, alkyl, alkoxy or -CD ₃ ;

R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring having 5 or 6 members. a fused heterocyclyl, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;

E is CH or CF;

X is CH or N;

Z is CH or N;

-CD ₃ is It is a fully deuterated methyl group,

However, both X and Z cannot be CH.

The moiety at R ₅ may be substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl or halogen.

Compounds of formula (I) may have the sulfoximine group in the R stereochemical configuration, the S stereochemical configuration, or a mixture of R and S stereochemical configurations.

C. Third set of compounds

In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.

here:

R ₁ is halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;

R ₂ is selected from the group consisting of aryl, heteroaryl and unsaturated heterocyclyl, where:

Each aryl, heteroaryl and unsaturated heterocyclyl is substituted into an optionally saturated carbocyclyl containing 5-6 ring members and an optionally saturated heterocyclyl containing 5-6 ring members and 1-3 heteroatoms. randomly fused to one selected from the group consisting of;

Each aryl, heteroaryl and unsaturated heterocyclyl is -(CH ₂ ) _n NR ^e C(O)N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ , -(CH ₂ ) _n NR ^e C(O)NR ^e R ^j , -(CH ₂ ) _n NR ^e C(O)OR ^j , -(CH ₂ ) _n NR ^e C(O)R ^j , -(CH ₂ ) _n NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ , -( CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m R ^j , alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl Ponyl, alkyl sulfoxide, alkyl sulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, -C(O)NH ₂ , -C(O)NR ^e R ^j , -C(O)R ^j , C ₁ -C ₄ alkoxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ cycloheteroalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -CN, -CO ₂ H, -CO ₂ R ^j , cyano, -H, halogen, heteroaryl, mono-, di- and trihalo-C ₁ -C ₄ Alkyl, mono-, di- or trihaloalkoxyl, morpholinyl, nitro, O-aryl, -OC(O)N(R ^j ) ₂ , -OC(O)NR ^e R ^j , -OC(O) R ^j , -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ cycloheteroalkyl, -OC ₃ -C ₆ cycloalkyl, -OH, O-heteroaryl, oxazolyl, Oxo, -S(O) ₂ R ^j , -SO ₂ aryl, -SO ₂ C ₁ -C ₆ alkenyl, -SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₂ -C ₆ cycloheteroalkyl, - SO ₂ C ₃ -C ₆ cycloalkyl, SO ₂ heteroaryl, -SO ₂ NH ₂ , -SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ alkyl, -SO ₂ NR ^e C ₂ - C ₆ alkenyl, -SO ₂ NR ^e C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H, -SR ^j , Sulfoximinyl -S(O)(=NR ^a )R ^a , Sulfonimidamide -S(O)(=NR ^a )N(R ^a ) ₂ , Sulfonimidoyl fluoride -S(O)(=NR ^a ) F and sulfondiimine -S (=NR ^a ) ₂ R ^a , wherein each of the alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl substituents is itself optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl) and -N(C ₁ -C ₆ alkyl) ₂ ;

unsaturated heterocyclyl is optionally substituted with R ^k R ^l ;

Each heteroatom in heteroaryl, unsaturated heterocyclyl, and optionally saturated heterocyclyl is independently O, S, or N(R ^h ) _q , each of which may be in its oxidized or non-oxidized state;

R ₃ is -H, cyano, halogen, C ₁ -C ₄ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ -C ₄ alkoxyl, optionally substituted C ₁ -C ₈ alkyl, and C ₃ -C ₈ cycloalkyl optionally substituted with 1-4 fluorine atoms;

Each R ^a is independently halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;

each R ^e is independently -H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl;

Each R ^h is independently -H, or C ₁ -C ₆ alkyl;

Each R ^j is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ cycloheteroalkyl, aryl, or ^heteroaryl , wherein Each of the alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, cyano, and -S(O) ₂ CH ₃ ;

R ^k and R ^l are Together with the atoms to which they are attached, they form a cycloalkyl or cycloheteroalkyl containing 3 to 7 ring members;

E is CH, CF or N;

Q is CH, CF or N;

T is CH, CF or N;

W is CH, CF or N;

X is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

Y is N or N ⁺ O ^- ;

Z is N, N ⁺ O ^- or CH;

Each m is independently 0-2;

Each n is independently 0-4;

Each q is independently 0 or 1.

R ₂ may be optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted unsaturated heterocyclyl.

R ₁ may be H, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl or halocycloalkyl.

R ₃ may be mono-, di-, or trihalo-C ₁ -C ₄ alkyl. R ₃ may be -CF ₃ .

E may be CH, CF or N.

Q may be CH, CF or N.

T may be CH, CF or N.

W may be CH, CF or N.

D. Fourth set of compounds

In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.

here:

R ₁ is halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;

R ₂ is selected from the group consisting of aryl, heteroaryl and unsaturated heterocyclyl, where:

Each aryl, heteroaryl and unsaturated heterocyclyl is substituted into an optionally saturated carbocyclyl containing 5-6 ring members and an optionally saturated heterocyclyl containing 5-6 ring members and 1-3 heteroatoms. randomly fused to one selected from the group consisting of;

Each aryl, heteroaryl and unsaturated heterocyclyl is -(CH ₂ ) _n NR ^e C(O)N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ , -(CH ₂ ) _n NR ^e C(O)NR ^e R ^j , -(CH ₂ ) _n NR ^e C(O)OR ^j , -(CH ₂ ) _n NR ^e C(O)R ^j , -(CH ₂ ) _n NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ , -( CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m R ^j , alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl Ponyl, alkyl sulfoxide, alkyl sulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, -C(O)NH ₂ , -C(O)NR ^e R ^j , -C(O)R ^j , C ₁ -C ₄ alkoxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ cycloheteroalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -CN, -CO ₂ H, -CO ₂ R ^j , cyano, -H, halogen, heteroaryl, mono-, di- and trihalo-C ₁ -C ₄ Alkyl, mono-, di- or trihaloalkoxyl, morpholinyl, nitro, O-aryl, -OC(O)N(R ^j ) ₂ , -OC(O)NR ^e R ^j , -OC(O) R ^j , -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ cycloheteroalkyl, -OC ₃ -C ₆ cycloalkyl, -OH, O-heteroaryl, oxazolyl, Oxo, -S(O) ₂ R ^j , -SO ₂ aryl, -SO ₂ C ₁ -C ₆ alkenyl, -SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₂ -C ₆ cycloheteroalkyl, - SO ₂ C ₃ -C ₆ cycloalkyl, SO ₂ heteroaryl, -SO ₂ NH ₂ , -SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ alkyl, -SO ₂ NR ^e C ₂ - C ₆ alkenyl, -SO ₂ NR ^e C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H, -SR ^j , Sulfoximinyl -S(O)(=NR ^a )R ^a , Sulfonimidamide -S(O)(=NR ^a )N(R ^a ) ₂ , Sulfonimidoyl fluoride -S(O)(=NR ^a ) F and sulfondiimine -S (=NR ^a ) ₂ R ^a , wherein each of the alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl substituents is itself optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl) and -N(C ₁ -C ₆ alkyl) ₂ ;

unsaturated heterocyclyl is optionally substituted with R ^k R ^l ;

Each heteroatom in heteroaryl, unsaturated heterocyclyl, and optionally saturated heterocyclyl is independently O, S, or N(R ^h ) _q , each of which may be in its oxidized or non-oxidized state;

R ₃ is -H, cyano, halogen, C ₁ -C ₄ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ -C ₄ alkoxyl, optionally substituted C ₁ -C ₈ alkyl, and C ₃ -C ₈ cycloalkyl optionally substituted with 1-4 fluorine atoms;

Each R ^a is independently halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;

each R ^e is independently -H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl;

Each R ^h is independently -H, or C ₁ -C ₆ alkyl;

Each R ^j is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ cycloheteroalkyl, aryl, or ^heteroaryl , wherein Each of the alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, cyano, and -S(O) ₂ CH ₃ ;

R ^k and R ^l are Together with the atoms to which they are attached, they form a cycloalkyl or cycloheteroalkyl containing 3 to 7 ring members;

E is CH or CF;

Q is CH, CF or N;

T is CH, CF or N;

W is CH, CF or N;

X is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

Y is N or N ⁺ O ^- ;

Z is N or N ⁺ O ^- ,

Each m is independently 0-2;

Each n is independently 0-4;

Each q is independently 0 or 1.

R ₂ may be optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted unsaturated heterocyclyl.

R ₁ may be H, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl or halocycloalkyl.

R ₃ may be mono-, di-, or trihalo-C ₁ -C ₄ alkyl. R ₃ may be -CF ₃ .

E may be CH, CF or N.

Q may be CH, CF or N.

T may be CH, CF or N.

W may be CH, CF or N.

E. Fifth set of compounds

In some aspects, the subject matter disclosed herein provides compounds of Formula (I) and pharmaceutically acceptable salts thereof.

here:

R ₁ is aryl or heteroaryl, wherein aryl or heteroaryl is unsubstituted or mono-, di-, and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di-, or trihaloalkoxyl, sulfanyl, trifluoro is substituted with one or more groups selected from the group consisting of methylsulfanyl, and arylalkoxyl;

R ₂ is selected from the group consisting of aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted. C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloal. substituted with one or more groups selected from the group consisting of coxyl, arylalkoxyl, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfanonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

R ₃ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ ;

R ₄ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or

R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached.

In some aspects of compounds of formula (I), R ₁ is phenyl or pyridinyl, where phenyl or pyridinyl is unsubstituted, or substituted or unsubstituted C ₁ -C ₈ alkyl, halogen, -OR ₅ (where R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is an integer selected from the group of 1, 2, 3, 4, 5, 6, 7, and 8), and - Substituted with one or more groups selected from the group consisting of S-CF ₃ ;

R ₂ is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, and 1,3- selected from the group consisting of benzothiazolyl, wherein phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, and 1,3-benzothiazolyl is unsubstituted, or unsubstituted or substituted C ₁ -C ₈ alkyl, halogen, cyano, oxo, -OR ₅ (where R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , and -CHF ₂ ), -(CH ₂ ) _q -OH (where q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8), - NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, -C(=O)-R ₈ (where R ₈ is -NR ₆ R ₇ (wherein R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkyl), -S(=O)-R ₉ , -S(=O) ₂ -R ₉ , -S(=O)(=NR ₁₀ )-R ₁₁ , and -N=S(=O)-(R ₁₁ ) ₂ with one or more groups selected from the group consisting of substituted, wherein each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ , or -NR ₆ R ₇ , wherein R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl. and R ₁₀ is H or C ₁ -C ₄ alkyl, R ₁₁ is C ₁ -C ₄ alkyl, provided that when Y is nitrogen and R ₂ is phenyl or pyridyl, R ₈ is -NR ₆ cannot be R ₇ ;

R ₃ is hydrogen, cyano, halogen, -CF ₃ , C ₁ -C ₈ alkoxyl, -O-CH(F) ₂ , substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl , -N ⁺ (=O)-O ^- is selected from the group consisting of;

R ₄ is selected from the group consisting of hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, -CF ₃ , substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ is not at the same time hydrogen; or

R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached.

In certain aspects, compounds of Formula (I) include compounds of Formula (II).

here:

R ₂ is selected from the group consisting of aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted. C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloal. substituted with one or more groups selected from the group consisting of coxyl, arylalkoxyl, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfanonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

R ₃ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ ;

R ₄ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or

R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached;

n is an integer selected from 0, 1, 2, 3, 4 and 5;

Each R ₂₄ is independently mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyanoalkyl. selected from the group consisting of gno, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl.

In some aspects of compounds of Formula (II), R ₂ is selected from the group consisting of:

here:

m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

R ₂₅ is H, morpholinyl, oxazolyl, halogen, cyano, -(CH ₂ ) _q -OH (where q is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8) is an integer), -C(=O)-R ₈ where R ₈ is selected from the group consisting of -NR ₆ R ₇ and C ₁ -C ₄ alkyl, where R ₆ and R ₇ are H and C ₁ -C ₄ selected from the group consisting of alkyl), -S(=O)-R ₉ , -S(=O) ₂ -R ₉ , -S(=O)(=NR ₁₀ )-R ₁₁ , and -N=S( =O)-(R ₁₁ ) ₂ (wherein each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ , or -NR ₆ R ₇ , where R ₆ and R ₇ are is selected from the group consisting of H and C ₁ -C ₄ alkyl, R ₁₀ is H or C ₁ -C ₄ alkyl, R ₁₁ is C ₁ -C ₄ alkyl, provided that Y is nitrogen and R ₂ is phenyl or In the case of pyridyl, R ₈ is -NR ₆ cannot be R ₇ );

R ₂₆ is halogen or cyano;

each R ₂₇ is independently selected from the group consisting of H, halogen, C ₁ -C ₈ alkoxyl, cyano, and -NR ₆ R ₇ ;

Each R ₂₈ is independently H or C ₁ -C ₄ alkyl.

In some aspects, compounds of Formula (I) include compounds of Formula (III).

here:

R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;

R ₂ is

is selected from the group consisting of;

R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ .

In some aspects, compounds of Formula (I) include compounds of Formula (IV).

R ₂ is selected from the group consisting of:

(i) ; where R _2b is selected from the group consisting of H, C ₁ -C ₄ alkyl, and halogen; R ₁₄ is C ₁ -C ₄ alkyl;

(ii) ; where R _5b is selected from the group consisting of -C(=O)-R ₈ , -(CH ₂ ) _n OH, and cyano, where R ₈ is C ₁ -C ₄ alkyl and n is 1, 2, 3 , is an integer selected from 4, 5, 6, 7 and 8;

(iii) , where R _5b' is selected from the group consisting of H, halogen, and C ₁ -C ₄ alkyl;

(iv) , where R _4b is H or halogen;

(v) , where R ₉ is H or C ₁ -C ₄ alkyl; and

(vi) .

F. How to use the compound

In another aspect, the invention provides inhibitors of the Na _V 1.8 sodium channel. The inhibitor may have a defined chemical structure, such as that of any of the compounds described above.

In another aspect, the invention provides a method of treating a condition in a subject having the condition by providing the subject with a compound of the invention, such as any of those described above.

The condition may be associated with abnormal activity of the Na _V 1.8 sodium channel. Conditions include abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute pruritus, acute pain, acute pain from major trauma/injury, airway hyperresponsiveness, allergic dermatitis, allergies, ankylosing spondylitis, asthma, atopy, Behcet's disease, bladder. Pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, biliary tract. Congestion, chronic cough, chronic itching, chronic back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndrome, persistent unilateral facial pain with additional attacks , contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, distal sensory polyneuropathy (DSP) associated with highly active antiretroviral therapy (HAART). , Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythrodynia, Fabry disease, facet joint syndrome, failed spinal surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain. , gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythroderma, irritable bowel syndrome, irritable bowel syndrome, itching, juvenile idiopathic arthritis, mastocytosis, adenoid hyperostosis, migraine, multiple sclerosis, musculoskeletal damage, fascia Orofacial pain, post-ischemic neurodegeneration, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, Osteoarthritis, overactive bladder, congenital onychohypertrophy, pain, pain due to cancer, pain due to chemotherapy, pain due to diabetes, pain syndrome, painful joint arthroplasty, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative. Pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, post-operative pain, post-stroke pain, post-operative pain, post-thoracotomy. Pain syndrome, post-traumatic stress disorder, preoperative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary glands. Pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, short pain, subacute cough, temporomandibular joint disorder, tension-type headache, trigeminal neuralgia, It may be a vascular leg ulcer, vulvodynia, or whiplash-related disorder. In another aspect, the invention provides a method of preparing a medicament using a compound of the invention, such as any of the above.

In another aspect, the invention provides a product comprising a compound of the invention, such as any of the above, for the treatment of a condition in a subject, such as any of the above.

A. Definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the subject matter described herein pertains. The definitions provided below are intended to supplement and illustrate, rather than exclude, definitions that will be apparent to those skilled in the art upon review of this disclosure.

Unless otherwise stated, the moieties described below are optionally substituted, that is, they may be substituted at one or more positions. As used herein, whether preceded by "optionally" or not, the term substituted and substituents refer to the ability to change one or more functional groups for another functional group or groups on a molecule, as long as the valency of all atoms is maintained. . If more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Substituents may also be further substituted (e.g., an aryl group substituent may have another substituent therefrom, such as another aryl group further substituted at one or more positions).

When the term “independently selected” is used, the substituents referred to (e.g., R groups such as groups R ^h , R ^j , etc., or variables such as “m” and “n”) may be the same or different. there is. For example, R ^h and R ^j can both be substituted alkyl, or R ^h can be hydrogen and R ^j can be substituted alkyl, etc.

The term singular, when used herein in relation to a group of substituents, means at least one. For example, when a compound is substituted with “one” alkyl or aryl, the compound is optionally substituted with one or more alkyl and/or one or more aryl. Moreover, when a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” When a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different.

Unless otherwise specified herein, a named “R” or group will have a structure generally recognized in the art to correspond to the group bearing that name. For purposes of illustration, certain representative “R” groups as described above are defined below.

The description of compounds of this disclosure is limited by the principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitution is in accordance with the principles of chemical bonding, is not inherently unstable, and/or is stable under ambient conditions such as aqueous, neutral, and various known physiological conditions. The selection is made to provide compounds that will be known to those skilled in the art as having the potential to be unstable under the conditions. For example, heterocycloalkyl or heteroaryl may be attached to the remainder of the molecule via a ring heteroatom according to principles of chemical bonding known to those skilled in the art to avoid inherently unstable compounds.

Unless explicitly defined otherwise, as used herein, “substituent group” includes a functional group selected from one or more of the following moieties as defined herein.

As used herein, the term hydrocarbon refers to any chemical group containing hydrogen and carbon. Hydrocarbons may be substituted or unsubstituted. As is known to those skilled in the art, in making any substitution all valencies must be met. Hydrocarbons may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Exemplary hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, etc. do.

The term "alkyl", by itself or as part of another substituent, means a straight-chain (i.e. unbranched) or branched, acyclic or cyclic saturated hydrocarbon group, or a combination thereof, unless otherwise stated; , may include divalent and multivalent groups having a specified number of carbon atoms (e.g., C _1-10 may include 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 carbons. refers to 1 to 10 carbons). In certain embodiments, the term “alkyl” refers to a 1, 2, 3, 4, 5, 6, 7, 8, 9, alkyl group derived by the removal of a single hydrogen atom from a hydrocarbon moiety containing 1 to 20 carbon atoms. , refers to a linear (i.e. "straight-chain"), branched, or cyclic saturated hydrocarbon radical containing C _1-10 containing 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons. do.

Representative saturated hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec- Includes, but is not limited to, hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers thereof.

“Branched” refers to an alkyl group having a lower alkyl group, such as methyl, ethyl or propyl, attached to a linear alkyl chain. “Lower alkyl” refers to an alkyl group having from 1 to about 8 carbon atoms (i.e., C _1-8 alkyl), for example, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. “Higher alkyl” refers to an alkyl group having from about 10 to about 20 carbon atoms, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

An alkyl group may be optionally substituted with one or more alkyl group substituents, which may be the same or different (“substituted alkyl”). The term “alkyl group substituent” includes alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, Includes, but is not limited to, oxo and cycloalkyl. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be optionally inserted along the alkyl chain, where the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl.

Accordingly, the term "substituted alkyl" means that one or more atoms or functional groups of an alkyl group are substituted with another atom or functional group, such as, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro. , amino, alkylamino, dialkylamino, sulfate, cyano and mercapto.

The term "heteroalkyl", by itself or in combination with another term, unless otherwise specified, refers to a stable straight or branched chain having 1 to 20 carbon atoms or heteroatoms, or 3 to 15 carbon atoms or heteroatoms. means a cyclic hydrocarbon group having, or a combination thereof, consisting of at least 1 carbon atom and at least 1 heteroatom, such as O, N, P, Si or S, where nitrogen, phosphorus and sulfur atoms are optional. It can be oxidized and the nitrogen heteroatoms can be optionally quaternized. The heteroatom(s) O, N, P and S and Si may be located at any internal position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples are -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ -CH ₂ -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ -CH=N-OCH ₃ , -CH=CH-N(CH ₃ )-CH ₃ , O-CH ₃ , -O-CH ₂ -CH ₃ , and -CN, but It is not limited. For example, up to 2 or 3 heteroatoms may be consecutive, such as -CH2-NH-OCH ₃ and -CH ₂ -O-Si(CH ₃ ) ₃ .

As described above, heteroalkyl groups as used herein are groups attached to the remainder of the molecule through a heteroatom, such as -C(O)NR', -NR'R", -OR', -SR, -S(O )R, and/or -S(O ₂ )R'.

“Cycloalkyl” refers to a saturated monocyclic or multicyclic ring system of from about 3 to about 15 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Cycloalkyl groups may also be optionally substituted with alkyl group substituents, oxo and/or alkylene, as defined herein. One or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms may be optionally inserted along the cyclic alkyl chain, wherein the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl or substituted aryl, and thus A heterocyclic group is provided. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc.

As used herein, the term "cycloalkylalkyl" also refers to a cycloalkyl group as defined above attached to the parent molecular moiety through an alkylene moiety, for example a C _1-20 alkylene moiety. do. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

The term “carbocyclyl” refers to a monocyclic or multicyclic ring system of about 3 to about 15 ring members where all ring members are carbon atoms. Unless otherwise specified, carbocyclyl can be saturated, partially saturated (i.e., has one or more double or triple bonds), or aromatic.

The term “heterocyclyl” refers to a monocyclic or multicyclic ring system of about 3 to about 15 ring members where at least one ring member is a heteroatom, such as N, O or S. Unless otherwise specified, heterocyclyls can be saturated, partially saturated (i.e., have one or more double or triple bonds), or aromatic. Examples of saturated and partially unsaturated non-aromatic heterocyclic groups include 3-oxetanyl, 2-oxetanyl, azetidinyl, thiethanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyra. Nyl, tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3-oxazinanyl, 1,3-thiazinanyl, 4 , 5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, tetrazolyl, imidazolyl , isothiozolyl, triazolyl, azabicyclo-octanyl, diazabicyclo-octanyl, and all alkyl, alkoxy, haloalkyl and haloalkoxy substituted derivatives of any of the above-mentioned groups. No.

The terms “cycloheteroalkyl” and “heterocycloalkyl” refer to a saturated ring system containing one or more heteroatoms, such as a 3- to 10-membered cycloalkyl ring system. The heteroatoms may be the same or different and may be nitrogen (N), oxygen (O), or sulfur (S). Examples of heterocycloalkyls are 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholyl. Includes polynyl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, etc. , but is not limited to this.

Cycloheteroalkyl rings may optionally be fused or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings. Heterocyclic rings include those having 1 to 3 heteroatoms, such as oxygen, sulfur and nitrogen, where the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatoms may be optionally quaternized. Examples include, but are not limited to, bi- or tri-cyclic groups comprising a fused 6-membered ring having 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, where (i) each The 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) The nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatoms may be optionally quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, and morpholy. Includes, but is not limited to, nyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, etc.

An unsaturated hydrocarbon, carbocyclyl or heterocyclyl, has one or more double or triple bonds. Examples of unsaturated hydrocarbons are vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), Includes, but is not limited to, thynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers.

As used herein, the term “alkenyl” refers to a monovalent group derived from a C _2-20 containing straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen molecule. Alkenyl groups include, for example, ethenyl (i.e. vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl. do.

As used herein, the term “cycloalkenyl” refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl. do.

As used herein, the term “alkynyl” refers to a monovalent group derived from a straight or branched C _2-20 hydrocarbon of the indicated number of carbon atoms containing at least one carbon-carbon triple bond. Examples of “alkynyl” include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, etc.

The term “alkylene”, by itself or as part of another substituent, refers to a group consisting of 1 to about 20 carbon atoms, for example 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12. , refers to a straight-chain or branched divalent aliphatic hydrocarbon group derived from an alkyl group having 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Alkylene groups can be straight-chain, branched, or cyclic. Alkylene groups may also be optionally unsaturated and/or substituted with one or more “alkyl group substituents.” One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”) may optionally be inserted along the alkylene group, where the nitrogen substituent is alkyl as described above. Exemplary alkylene groups include methylene (-CH ₂ -); ethylene (-CH ₂ -CH ₂ -); Propylene (CH ₂ ) ₃ , Cyclohexylene (-C ₆ H ₁₀ -, -CH=CH-CH=CH-, -CH=CH-CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH(CH ₂ CH ₂ CH ₃ )CH ₂ -, -(CH ₂ ) _q -N(R)-(CH ₂ ) _r - (where each q and r is independently from 0 to about 20 An integer, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, R is hydrogen or lower alkyl); methylenedioxyl (-O-CH ₂ -O-); and ethylenedioxyl (-O-(CH ₂ ) ₂ -O-).

The term “heteroalkylene” by itself or as part of another substituent refers to a divalent group derived from heteroalkyl, including but not limited to -CH ₂ -CH ₂ -S-CH ₂ -CH ₂ - and -CH ₂ -S-CH ₂ -CH ₂ -NH-CH ₂ -. For heteroalkylene groups, heteroatoms may also occupy one or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linkages, no orientation of the linkage group is implied by the direction in which the formula of the linkage group is written. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

The term “spirocyclyl” refers to a polycyclic compound in which two rings have a single atom, such as carbon, as the only common member of the two rings. Thus, "spirocycloalkyl" refers to a cycloalkyl group having two rings having a single carbon in common, and "spiroheterocycloalkyl" or "spiroheterocycloalkyl" refers to a cycloalkyl group having two rings in common having a single carbon or another atom, e.g. Refers to a cycloheteroalkyl group having two rings bearing nitrogen.

The term “aryl,” unless otherwise stated, refers to an aromatic hydrocarbon substituent that may be a single ring or multiple rings fused together or covalently linked (e.g., 1 to 3 rings).

The term “heteroaryl” refers to a group (or ring) containing 1 to 4 heteroatoms (in each individual ring in the case of multiple rings) selected from N, O and S, wherein the nitrogen and sulfur atoms are optional. oxidized, and the nitrogen atom(s) are optionally quaternized. Heteroaryl groups can be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imy. Dazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- Isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl , 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, Includes 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. Substituents for each of the aryl and heteroaryl ring systems mentioned above are selected from the group of acceptable substituents described below. The terms “arylene” and “heteroarylene” refer to the divalent forms of aryl and heteroaryl, respectively.

When the heteroalkyl, heterocycloalkyl or heteroaryl contains a specific number of members (e.g., “3 to 7 members”), the term “member” refers to a carbon atom or heteroatom.

Each of the above terms is intended to include both substituted and unsubstituted forms of the groups indicated. Optional substituents are provided below.

Substituents are -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R", -OC(O)R, -C( O)R, -CO ₂ R -C(O)NR'R", -OC(O)NR'R", -NR"C(O)R, -NR'-C(O)NR"R"' , -NR"C(O)OR', -NR-C(NR'R")=NR"', -S(O)R, -S(O) ₂ R', -S(O) ₂ NR'R", -NRSO ₂ R', -CN, CF ₃ , fluorinated C _1-4 alkyl, and -NO ₂ a number ranging from 0 to (2m' +1), where m' is the carbon atom in this group It may be one or more of a variety of groups selected, but not limited to, (the total number of). R', R", R"' and R"" are each independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl. (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. Other non-limiting examples of substituents include (C ₁ -C ₆ )alkyl, (C ₂ -C ₈ )alkenyl, (C ₃ -C ₈ )alkynyl, halogen, halo(C ₁ -C ₆ )alkyl, hydroxy. , -O(C ₁ -C ₆ )alkyl, halo(C ₁ -C ₆ )alkoxy, (C ₃ -C ₈ )cycloalkyl, (C ₆ -C ₁₀ )aryl, heterocyclyl, heteroaryl, amino, Cyano, nitro, (C ₁ -C ₆ )alkyl-OH, (C ₁ -C ₆ )alkyl-O-(C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkyl(C ₆ -C ₁₀ )aryl, -C(O)(C ₁ -C ₆ )alkyl, -C(O)NR'R", -S(O)(C ₁ -C ₆ )alkyl, -S(O)NR'R" , -S(O) ₂ (C ₁ -C ₆ )alkyl, -S(O) ₂ NR'R", -O(C ₁ -C ₆ )alkyl-S(O)(C ₁ -C ₆ )alkyl , -O(C ₁ -C ₆ )alkyl-S(O)NR'R", -O(C ₁ -C ₆ )alkyl-S(O) ₂ (C ₁ -C ₆ )alkyl and -O(C ₁ -C ₆ )alkyl-S(O) ₂ NR'R". As used herein, an "alkoxy" group is an alkyl attached to the remainder of the molecule through a divalent oxygen.

When a compound of the disclosure comprises more than one R group, e.g. when more than one of these groups is present, each R group independently represents each of R', R", R"' and R It is selected like "". When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will understand that the term “alkyl” refers to groups containing a carbon atom bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF ₃ and -CH ₂ CF ₃ ) and acyl ( For example, -C(O)CH ₃ , -C(O)CF ₃ , -C(O)CH ₂ OCH ₃ , etc.).

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally form a ring of the formula -TC(O)-(CRR') _q -U-, where T and U are independently -NR-, - O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with substituents of the formula -A-(CH2) _r -B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ NR'- or a single bond, and r is an integer from 1 to 4.

One of the single bonds of the new ring formed in this way can optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by substituents of the formula -(CRR')s-X'-(C"R"')d-, where s and d is independently an integer from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) ₂ -, or -S(O) ₂ NR '-am. Substituents R, R', R" and R" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or It may be selected from unsubstituted heteroaryl.

As used herein, the term "acyl" refers to an organic acid group in which -OH of the carboxyl group is replaced by another substituent and has the formula RC(=O)-, where R is alkyl, alkenyl, as defined herein. , alkynyl, aryl, carbocyclic, heterocyclic or aromatic heterocyclic groups. Accordingly, the term “acyl” specifically includes aryl acyl groups such as 2-(furan-2-yl)acetyl)- and 2-phenylacetyl groups. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides, -RC(=O)NR, esters, -RC(=O)OR', ketones, -RC(=O)R', and aldehydes, -RC(=O)H. do.

The terms “alkoxyl” or “alkoxy” are used interchangeably herein and are saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl) attached to the parent molecular moiety through an oxygen atom. -O-) group, where the terms "alkyl", "alkenyl" and "alkynyl" are as defined above and include, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, May contain linear, branched or cyclic, saturated or unsaturated oxo-hydrocarbon chains containing C _1-20 , including sec-butoxyl, tert-butoxyl and n-pentoxyl, neopentoxyl, n-hexoxyl, etc. there is.

As used herein, the term “alkoxy alkyl” refers to an alkyl-O-alkyl ether, such as a methoxy ethyl or ethoxymethyl group.

“Aryloxyl” refers to the group aryl-O-, where aryl groups are as previously described, including substituted aryl. As used herein, the term “aryloxyl” can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo or alkoxyl substituted phenyloxyl or hexyloxyl.

“Aralkyl” refers to the group aryl-alkyl-, where aryl and alkyl are as previously described and include substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

“Aralkyloxyl” refers to the aralkyl-O- group, where the aralkyl group is as previously described. An example of an aralkyloxyl group is benzyloxyl, ie C ₆ H ₅ CH ₂ -O-. Aralkyloxyl groups may be optionally substituted.

“Alkoxycarbonyl” refers to the group alkyl-O-C(=O)-. Exemplary alkoxy carbonyl groups include methoxycarbonyl, ethoxy carbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.

“Aryloxycarbonyl” refers to the group aryl-O-C(=O)-. Exemplary aryloxy carbonyl groups include phenoxy- and naphthoxy-carbonyl.

“Aralkoxycarbonyl” refers to the aralkyl -O-C(=O)- group. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

“Carbamoyl” refers to an amide group of the formula -C(=O)NH ₂ .

“Alkylcarbamoyl” refers to the group R'RN -C(=O) wherein one of R and R' is hydrogen and the other of R and R' is alkyl and/or substituted alkyl as previously described . “Dialkylcarbamoyl” refers to the group R'RN-C(=O)-, where each R and R' is independently an alkyl and/or substituted alkyl as described above.

As used herein, the term “carbonyldioxyl” refers to a carbonate group of the formula -OC(=O)-OR.

“Acyloxyl” refers to an acyl-O- group where the acyl is as previously described.

The term “amino” refers to the group -NH ₂ and also to nitrogen-containing groups, as known in the art, derived from ammonia by replacement of one or more hydrogen radicals with organic groups. For example, the terms “acylamino” and “alkylamino” refer to certain N-substituted organic groups having acyl and alkyl substituents, respectively.

As used herein, “aminoalkyl” refers to an amino group covalently attached to an alkylene linker. More particularly, as used herein, the terms alkylamino, dialkylamino and trialkylamino each refer to 1, 2 or 3 alkyl groups as defined above attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', where R' is an alkyl group as defined above; The term dialkylamino refers to a group having the structure -NR'R", where R' and R" are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R"R"', where R', R", and R"' are each independently selected from the group consisting of an alkyl group. Additionally, R', R", and/or R"' together can optionally be -(CH ₂ ) _k , where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropyl amino, piperidino, trimethylamino, and propylamine.

The amino group is -NR'R", where R' and R" are typically hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclo is selected from alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The terms alkylthioether and thioalkoxyl refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) groups attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, etc.

“Acylamino” refers to an acyl-NH- group where the acyl is as previously described. “Aroylamino” refers to the group aroyl-NH- where aroyl is as previously described.

The term “carbonyl” refers to the group -C(=O)- and may include aldehyde groups represented by the formula R-C(=O)H.

The term “carboxyl” refers to the COOH group. These groups are also referred to herein as “carboxylic acid” moieties.

The term “cyano” refers to the group -CN.

The terms “halo,” “halide,” and “halogen” refer to fluoro, chloro, bromo, and iodo groups.

The term “haloalkyl” refers to an alkyl group substituted with one or more halogens. Additionally, the term “haloalkyl” includes monohaloalkyl and polyhaloalkyl. For example, the term “halo(C _1-4 )alkyl” includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. does not

The terms “halocycloalkyl” and “cyclohaloalkyl” refer to a cycloalkyl group having one or more halogens.

The term “hydroxyl” refers to the group -OH.

The term “hydroxy alkyl” refers to an alkyl group substituted with an -OH group.

The term “mercapto” refers to the group -SH.

The term “oxo” refers to an oxygen atom double bonded to a carbon atom or another element.

The term “nitro” refers to the -NO ₂ group.

The term “thio” refers to compounds previously described herein in which a carbon or oxygen atom is replaced by a sulfur atom.

The term “sulfate” refers to the -SO ₄ group.

As used herein, the term thiohydroxyl or thiol refers to a group of the formula -SH.

More particularly, the term “sulfide” refers to a compound having a group of the formula -SR.

The term “sulfone” refers to a compound having a sulfonyl group -S(O ₂ )R'.

The term “sulfoxide” refers to a compound having a sulfinyl group -S(O)R.

The term ureido refers to the urea group of the formula -NH-CO-NH ₂ .

When the heteroalkyl, heterocycloalkyl or heteroaryl contains a specific number of members (e.g., “3 to 7 members”), the term “member” refers to a carbon or heteroatom.

Additionally, as generally used herein, the structure represented by the formula

aliphatic and/or aromatic cyclic compounds containing substituent R groups, such as, but not limited to, 3-carbon, 4-carbon, 5-carbon, 6-carbon, 7-carbon, etc. ring structures, partially saturated ring structures, Refers to ring structures, and including unsaturated ring structures, wherein the R groups may be present or absent, and when present, one or more R groups may each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of R groups and the number of R groups are determined by the value of the variable “n”, which is generally an integer with values ranging from 0 to the number of carbon atoms on the ring available for substitution. Each R group, if more than one, is substituted on an available carbon of the ring structure rather than on another R group. For example, the above structures where n is 0 to 2 include, but are not limited to, compound groups:

It will include etc.

Dashed lines representing bonds in cyclic ring structures indicate that the bonds may be present or absent in the ring. That is, the dashed line representing the bond in the cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

sign ( ) indicates the point of attachment of the moiety to the rest of the molecule.

When a named atom of an aromatic ring or heterocyclic aromatic ring is defined as “absent,” the named atom is replaced by a direct bond.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl, and “heterocycloalkyl,” “aryl,” “heteroaryl,” “phosphonate,” and “sulfonate” as well as well as divalent derivatives thereof) are intended to include both substituted and unsubstituted forms of the groups indicated.Optional substituents for each type of group are provided below.

Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl monovalent and divalent derivative groups (often alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkyl). Substituents for (including groups referred to as alkenyl) are -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R"',-OC(O)R',-C(O)R', -CO ₂ R',-C(O)NR'R", -OC(O)NR'R", -NR"C(O )R', -NR'-C(O)NR"R"', -NR"C(O)OR', -NR-C(NR'R")=NR"', -S(O)R' , -S(O) ₂ R', -S(O) ₂ NR'R", -NRSO ₂ R', -CN, CF ₃ , 0 to (2m' from fluorinated C _1-4 alkyl and -NO ₂ +l) number in the range (where m' is the total number of carbon atoms in such group). R', R", R"' and R"" are each independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl. (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. As used herein, an “alkoxy” group is an alkyl attached to the remainder of the molecule through a divalent oxygen. When a compound of the disclosure comprises more than one R group, e.g. when more than one of these groups is present, each R group independently represents each of R', R", R"' and R It is selected like "". When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is Intended to include, but are not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will understand that the term “alkyl” refers to groups containing a carbon atom bonded to a group other than a hydrogen group, such as haloalkyl (e.g., -CF ₃ and -CH ₂ CF ₃ ) and acyl ( For example, -C(O)CH ₃ , -C(O)CF ₃ , -C(O)CH ₂ OCH ₃ , etc.).

Similar to the substituents described for alkyl groups above, exemplary substituents for aryl and heteroaryl groups (as well as their divalent derivatives) are diverse, such as halogen, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO ₂ R', -C(O)NR'R", -OC(O)NR'R" , -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)OR', -NR-C(NR'R"R"')=NR "", -NR-C(NR'R")=NR"'-S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R", -NRSO ₂ R' , -CN and -NO ₂ , -R', -N ₃ , -CH(Ph) ₂ , fluoro(C _1-4 )alkoxo, and fluoro(C _1-4 )alkyl, 0 to aromatic ring The total number of open valences on the system is selected as the number of ranges; where R', R", R"' and R"" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl , substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the disclosure comprises more than one R group, e.g. when more than one of these groups is present, each R group independently represents each of R', R", R"' and R It is selected like "".

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring can optionally form a ring of the formula -TC(O)-(CRR') _q -U-, where T and U are independently -NR-, - O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with substituents of the formula -A-(CH ₂ ) _r -B-, where A and B are independently -CRR'- , -O-, -NR-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ NR'- or a single bond, and r is an integer from 1 to 4. .

One of the single bonds of the new ring formed in this way can optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by substituents of the formula -(CRR') _s -X'-(C"R"') _d -, where s and d is independently an integer from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) ₂ -, or -S(O) ₂ NR '-am. Substituents R, R', R" and R"' are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

As used herein, the term "acyl" refers to an organic acid group in which -OH of the carboxyl group is replaced by another substituent and has the formula RC(=O)-, where R is alkyl, alkenyl, as defined herein. , alkynyl, aryl, carbocyclic, heterocyclic or aromatic heterocyclic groups. Accordingly, the term “acyl” specifically includes arylacyl groups such as 2-(furan-2-yl)acetyl)- and 2-phenylacetyl groups. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups also include amides, -RC(=O)NR', esters, -RC(=O)OR', ketones, -RC(=O)R', and aldehydes, -RC(=O)H. It is intended.

The terms “alkoxyl” or “alkoxy” are used interchangeably herein and are saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl) attached to the parent molecular moiety through an oxygen atom. -O-) group, wherein the terms "alkyl", "alkenyl" and "alkynyl" are as previously described and include, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl , sec-butoxyl, tert-butoxyl and may contain linear, branched or cyclic, saturated or unsaturated oxo-hydrocarbon chains containing C _1-20 , including n-pentoxyl, neopentoxyl, n-hexoxyl, etc. You can.

As used herein, the term “alkoxyalkyl” refers to an alkyl-O-alkyl ether, such as a methoxyethyl or ethoxymethyl group.

“Aryloxyl” refers to the group aryl-O-, where aryl groups are as previously described, including substituted aryl. As used herein, the term “aryloxyl” can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, halo or alkoxyl substituted phenyloxyl or hexyloxyl.

“Aralkyl” refers to the group aryl-alkyl-, where aryl and alkyl are as previously described and include substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

“Aralkyloxyl” refers to the aralkyl-O- group, where the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl, C ₆ H ₅ -CH ₂ -O-. Aralkyloxyl groups may be optionally substituted.

“Alkoxycarbonyl” refers to the group alkyl-O-C(=O)-. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.

“Aryloxycarbonyl” refers to the group aryl-O-C(=O)-. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

“Aralkoxycarbonyl” refers to the group aralkyl-O-C(=O)-. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

“Carbamoyl” refers to an amide group of the formula -C(=O)NH ₂ . "Alkylcarbamoyl" refers to the group R'RN-C(=O)- wherein one of R and R' is hydrogen and the other of R and R' is alkyl and/or substituted alkyl as previously described. do. “Dialkylcarbamoyl” refers to the group R'RN-C(=O)-, where each R and R' is independently an alkyl and/or substituted alkyl as described above.

As used herein, the term carbonyldioxyl refers to a carbonate group of the formula -O-C(=O)-OR.

“Acyloxyl” refers to an acyl-O- group where the acyl is as previously described.

The term “amino” refers to the group -NH ₂ and also to nitrogen-containing groups, as known in the art, derived from ammonia by replacement of one or more hydrogen radicals with organic groups. For example, the terms “acylamino” and “alkylamino” refer to certain N-substituted organic groups having acyl and alkyl substituents, respectively.

As used herein, “aminoalkyl” refers to an amino group covalently attached to an alkylene linker. More particularly, as used herein, the terms alkylamino, dialkylamino and trialkylamino each refer to 1, 2 or 3 alkyl groups as defined above attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', where R' is an alkyl group as defined above; The term dialkylamino refers to a group having the structure -NR'R", where R' and R" are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R"R"', where R', R", and R"' are each independently selected from the group consisting of an alkyl group. Additionally, R', R", and/or R"' together can optionally be -(CH ₂ ) _k -, where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.

The amino group is -NR'R", where R' and R" are typically hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclo is selected from alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

The terms alkylthioether and thioalkoxyl refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) groups attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, etc.

“Acylamino” refers to an acyl-NH- group where the acyl is as previously described. “Aroylamino” refers to the group aroyl-NH- where aroyl is as previously described.

The term “carbonyl” refers to the group -C(=O)- and may include aldehyde groups represented by the formula R-C(=O)H.

The term “carboxyl” refers to the group -COOH. These groups are also referred to herein as “carboxylic acid” moieties.

The term “cyano” refers to the group -C≡N.

As used herein, the terms “halo,” “halide,” or “halogen” refer to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl” are intended to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C _1-4 )alkyl” includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. It is not intended.

The term “hydroxyl” refers to the group -OH.

The term “hydroxyalkyl” refers to an alkyl group substituted with an -OH group.

The term “mercapto” refers to the group -SH.

As used herein, the term “oxo” refers to an oxygen atom double bonded to a carbon atom or another element containing the nitrogen of the pyridine ring to produce pyridine N-oxide.

The term “nitro” refers to the group -NO ₂ , which can also be represented as -N ⁺ (=O)-O ^- .

The term “thio” refers to compounds previously described herein in which a carbon or oxygen atom is replaced by a sulfur atom.

The term “sulfate” refers to the -SO ₄ group.

As used herein, the term thiohydroxyl or thiol refers to a group of the formula -SH.

More particularly, the term “sulfide” refers to a compound having a group of the formula -SR.

The term “sulfone” refers to a compound having a sulfonyl group -S(O ₂ )R.

The term “sulfoxide” refers to a compound having a sulfinyl group -S(O)R.

The term ureido refers to the urea group of the formula -NH-CO-NH ₂ .

Throughout the specification and claims, a given formula or name will encompass all tautomers, homologs, and optical- and stereoisomers, as well as racemic mixtures in which such isomers and mixtures exist.

Throughout the specification and claims, a given formula or name will encompass all tautomers, homologs, and optical- and stereoisomers, as well as racemic mixtures in which such isomers and mixtures exist.

Certain compounds of the present disclosure may possess asymmetric carbon atoms (optical or chiral centers) or double bonds; Enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined for an amino acid as (R)- or (S)- or D- or L- in the terms of absolute stereochemistry; and individual isomers are encompassed within the scope of this disclosure. Compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and/or isolate. The present disclosure is intended to include compounds in racemic, non-racemic and optically pure forms. The optically active (R)- and (S)-, or D- and L-isomers, can be prepared using chiral monomers or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

Unless otherwise stated, structures depicted herein also include all stereochemical forms of the structure; That is, it is intended to include R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are within the scope of this disclosure.

It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and that all such tautomeric forms of the compounds are within the scope of the present disclosure. As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

Unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the invention in which the hydrogen is replaced by deuterium or tritium, or in which the carbon is replaced by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure.

Compounds of the present disclosure may also contain non-natural proportions of atomic isotopes in one or more of the atoms comprising such compounds. For example, a compound may be radiolabeled with a radioactive isotope, such as, for example, deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ¹²⁵ I) or carbon-14 ( ^14C ). All isotopic modifications of the compounds of this disclosure, whether radioactive or not, are encompassed within the scope of this disclosure.

The compounds of the present disclosure may exist as salts, especially pharmaceutically acceptable salts. This disclosure includes such salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g. (+)-tartrate, (-) -tartrate, or racemic mixtures, succinates, benzoates, and mixtures thereof including salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Base addition salts such as sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts are also included. When compounds of the disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent or by ion exchange. Examples of acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or derived from phosphorous acid, etc., as well as organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid. , citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain specific compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted to base or acid addition salts.

The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner.

The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

Certain compounds of the present disclosure may exist in unsolvated forms as well as solvated forms, such as hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of this disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by this disclosure and are intended to be within the scope of this disclosure.

In addition to salt forms, the present disclosure provides compounds that are in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Additionally, prodrugs can be converted to compounds of the present disclosure by chemical or biochemical methods in an in vitro environment. For example, a prodrug can be slowly converted to a compound of the disclosure when placed in a transdermal patch reservoir with suitable enzymes or chemical reagents.

The term “protecting group” refers to a chemical moiety that blocks some or all reactive moieties of a compound and prevents these moieties from participating in a chemical reaction until the protecting group is removed, see, e.g., T. W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). If different protecting groups are used, it may be advantageous for each (different) protecting group to be removable by different means. Protecting groups that are cleaved under completely different reaction conditions enable differential removal of these protecting groups.

For example, protecting groups can be removed by acids, bases and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile, carboxy and hydroxy reactive moieties in the presence of amino groups protected by hydrogenolytically removable Cbz groups and base labile Fmoc groups. Can be used to protect tee. Carboxylic acid and hydroxy reactive moieties can be formed with acid labile groups such as tert-butyl carbamate or in the presence of amines blocked with carbamates that are both acid and base stable but removable by hydrolysis, with base labile groups such as Can be blocked with, but not limited to, methyl, ethyl and acetyl.

Carboxylic acid and hydroxy reactive moieties can also be blocked with hydrolytically removable protecting groups, such as the benzyl group, and amine groups capable of hydrogen bonding with acids can be blocked with base labile groups, such as Fmoc. The carboxylic acid reactive moiety can be blocked with an oxidatively removable protecting group such as 2,4-dimethoxybenzyl, while the coexisting amino group can be blocked with a fluoride labile silyl carbamate.

Allyl blocking groups are useful in the presence of acid- and base-protecting groups because the former is stable and can be subsequently removed by metal or pi-acid catalysts. For example, allyl-blocked carboxylic acids can be deprotected in a palladium(O)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Another type of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional groups can react.

Typical blocking/protecting groups include, but are not limited to, the following moieties:

In accordance with longstanding patent law practice, the terms singular, singular, when used in this application, including the claims, refer to “one or more.” Thus, for example, reference to “a subject” includes a plurality of subjects, etc., unless the context clearly dictates the contrary (e.g., a plurality of subjects).

Throughout this specification and claims, the terms “comprise,” “includes,” and “comprising” are used in a non-exclusive sense, except where the context otherwise requires. Likewise, the term "comprise" and its grammatical variations are intended to be non-limiting, and thus mention of an item in a list does not exclude other similar items that may be substituted for or added to the listed item.

For the purposes of this specification and the appended claims, unless otherwise indicated, amounts, sizes, dimensions, proportions, shapes, formulations, parameters, percentages, amounts, characteristics, and other numerical values used in the specification and claims are expressed. All numerical values given should be understood in all instances to be modified by the term “about” even if the term “about” may not be explicitly indicated as a value, quantity or range. Accordingly, unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims are not and are not required to be exact, but are intended to be consistent with tolerances, conversion factors, rounding, measurement errors, etc., and for the purposes to be achieved by the subject matter disclosed herein. Depending on the characteristics, it may be larger or smaller depending on the approximate and/or purpose, reflecting other factors known to those skilled in the art. For example, the term “about” when referring to a value, in some embodiments ± 100%, in some embodiments ± 50%, in some embodiments ± 20%, in some embodiments ± 10%, from a specified amount. %, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1%, which may be intended to encompass variations of This is because it is suitable for carrying out the method or using the disclosed composition.

Additionally, the term "about", when used in connection with one or more numbers or numerical ranges, refers to all such numbers, including all numbers within the range, and extends the boundaries of that range above and below the given numerical values. It should be understood as modifying . References to a numerical range by endpoints refer to all numbers, e.g., whole integers including their fractions contained within the range (e.g., references to 1 to 5 refer to 1, 2, 3, 4, and 5, as well as their fractions). includes fractions, such as 1.5, 2.25, 3.75, 4.1, etc.) and any ranges within that range.

compound

The present invention provides compounds that modulate, for example inhibit, the activity of voltage-gated Na _V 1.8 sodium channels.

A. First set of compounds

In certain embodiments, the compound has the structure of Formula (I) or a pharmaceutically acceptable salt thereof.

here:

R ₁ is an optionally substituted 5 or 6 ring-membered ring comprising -CN, -CF ₃ , an aryl or heteroaryl ring, wherein the 5 or 6 ring-membered ring optionally contains one or more N or S in the ring; , Substitution on the 5 or 6 ring member ring is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring has 5 or is selected from fused heterocyclyl with 6 members, heteroaryl with 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

R ₃ is halogen, alkyl or alkoxy;

R ₄ is halogen, alkyl or H;

R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring having 5 or 6 members. a fused heterocyclyl, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;

X is CH or N;

Z is CH or N,

However, both X and Z cannot be CH.

R ₂ may be -CH ₃ , -CD ₃ , or -CT ₃ where D is deuterium and T is tritium.

R ₃ may be -CH ₃ , -CD ₃ , or -CT ₃ where D is deuterium and T is tritium.

The moiety at R ₅ may be substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl or halogen.

Compounds of formula (I) may have the sulfoximine group in the R stereochemical configuration, the S stereochemical configuration, or a mixture of R and S stereochemical configurations.

In certain embodiments, the compound has the structure of Formula (II) or a pharmaceutically acceptable salt thereof.

here:

Each of J ₁ , J ₂ , J ₄ , and J ₅ is independently N, NO, or CR ₆ ;

J ₃ is N, NO, or CR ₇ ;

X is CH or N;

Y is NR ₈ or O;

Z is CH, N or N-O,

R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;

Each occurrence of R ₆ is independently H, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, CD ₃ or CT ₃ ;

R ₇ is H, halogen, -CD ₃ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, -CF ₃ , -OCF ₃ , each ring has 5 or heterocyclyl having 6 members, heteroaryl having 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, each ring having 5 or 6 members, O-aryl, each O-heteroaryl, O-cycloalkyl, O-cycloheteroalkyl, wherein the ring has 5 or 6 members, each of which is optionally substituted as valence permits;

R ₈ is H, C _1-3 alkyl, or C _3-5 cycloalkyl,

step,

X and Z cannot both be CH;

Two or less of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO.

R ₂ may be -CH ₃ , -CD ₃ , or -CT ₃ where D is deuterium and T is tritium.

Compounds of formula (II) may have the sulfoximine group in the R stereochemical configuration, the S stereochemical configuration, or a mixture of R and S stereochemical configurations.

In certain embodiments, the compound has the structure of Formula (III) or a pharmaceutically acceptable salt thereof.

here:

Each of J ₁ , J ₂ , J ₄ , and J ₅ is independently N, NO, or CR ₆ ;

J ₃ is N, NO, or CR ₇ ;

Each W ₁ , W ₂ , W ₃ , W ₄ , and W ₅ is independently N, CH, or CR ₉ ;

X is CH or N;

Z is CH, N or N-O,

Each occurrence of R ₆ is independently -H, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, CD ₃ or CT ₃ ;

R ₇ is -H, halogen, -CD ₃ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, -CF ₃ , -OCF ₃ , each ring Carbocyclyl with 3 to 6 members, heterocyclyl with each ring having 5 or 6 members, heteroaryl with 5 or 6 ring members, saturated hetero, with each ring having 3 to 6 members. Cycryl, or partially unsaturated heterocyclyl, O-aryl, each ring having 5 or 6 members, O-heteroaryl, each ring having 5 or 6 members, O-cycloalkyl, O-cyclohetero alkyl, each of which is optionally substituted where valency permits,

R ₉ in each case is independently -C(O)NR ₁₀ R ₁₁ , -S(O) ₂ C _1-6 alkyl, -S(O)(NH)C _1-6 alkyl, C _1-3 alkyl, or C _3-5 cycloalkyl;

Each R ₁₀ and R ₁₁ is independently selected from -H and C _1-5 alkyl, or R ₁₀ and R ₁₁ together with the nitrogen atom to which they are attached form a heterocyclyl having 3-6 members. and wherein each C _1-5 alkyl and heterocyclyl are optionally substituted if valency permits,

step,

Up to two of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO;

At most two of W ₁ , W ₂ , W ₃ , W ₄ and W ₅ are N;

Three or fewer of W ₁ , W ₂ , W ₃ , W ₄ and W ₅ are CR ₉ ;

X and Z cannot both be CH.

Compounds of the invention may be isotopically enriched at any position unless the atomic mass is otherwise specified. For example, a compound may have one or more hydrogen atoms replaced with a deuterium atom or a tritium atom. Isotopic substitution or enrichment may occur at carbon, sulfur or phosphorus, or other atoms. For example, and not by way of limitation, a fluorine atom may be ¹⁹ F-rich, a carbon atom may be ¹⁴ C-rich, and a nitrogen atom may be ¹⁵ N-rich. A compound may be isotopically substituted or enriched for a given atom at one or more positions within the compound, or a compound may be isotopically substituted or enriched at all occurrences of a given atom within the compound.

In certain embodiments, the compound has the structure of Formula (IV).

here:

Y is N or CR ₁₃ ;

A and B are independently aryl, heteroaryl, or a 3-6 membered ring containing one or more heteroatoms independently selected from O, S, and N; where A is unsubstituted or:

H, halo, C1-C6-alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, SR', -CH ₂ -cycloalkyl, -CF ₂ - Cycloalkyl, -CH(CH ₃ )-cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH(-CH ₃ )-aryl, C(=O)-alkyl, -C(=O)cyclo Alkyl, -C(=O)-NH-alkyl, -C(=O)NH ₂ , hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR'R"-NHSOR', -NHC(=O)-alkyl -NH(C=O)NR'R", SO ₂ R', trifluoromethyl, bromo, chloro, fluoro, cyclopropylmethyl, sulfonylmethyl, 3-6 membered cycloalkyl; is substituted with one or more substituents selected from 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl is independently selected from O, S, and N. contains at least one heteroatom;

R ₁₂ , R ₁₃ and R ₁₄ are individually selected from H, CF ₃ , halo, C1-C6-alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano; -CH ₂ -cycloalkyl, -CF ₂ -cycloalkyl, -CH(CH ₃ )-cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH(-CH ₃ )-aryl, C(=O )-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH ₂ , hydroxy, -COOH (and esters thereof), alkylsulfonyl, aryl sulphenyl Ponyl, sulfonamide, amino, NR'R" -NHSO ₂ R1, -NHC(=O)-alkyl -NH(C=O)NR'R", spirocyclyl, morpholinyl, pyrrolidinyl, piperidi selected from nyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein the 5 or 6 ring member ring optionally contains one or more N or S within the ring, and wherein substitution on the 5 or 6 ring member ring Silver halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, -C(=O)-NH-alkyl, -C(=O)NH ₂ cyano, CF ₃ , CHF ₂ , OCH ₃ , OCF ₃ , fused heterocyclyl with each ring having 5 or 6 members, heteroaryl with 5 or 6 ring members, saturated heterocyclyl or partially unsaturated heterocyclyl. and each of these is optionally substituted if valency permits;

Substituents R' and R" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. , or from CD ₃ can be selected.

In selected embodiments, A is CH ₂ CF ₃ or am.

In another aspect, the invention provides compounds of formula (V).

here

A and B are as described for formula (IV);

R ₂ is as described for formula (II);

R ₁₃ and R ₁₄ are as described in formula (IV);

X is CH or N;

Y is NR ₈ or O;

Z is CH, N or N-O.

B. Second set of compounds

The compound has the structure of formula (I) or a pharmaceutically acceptable salt thereof.

here:

R ₁ is -CN or -CF ₃ ;

R ₃ is halogen, alkyl, alkoxy or -CD ₃ ;

R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring having 5 or 6 members. a fused heterocyclyl, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;

E is CH or CF;

X is CH or N;

Z is CH or N;

-CD ₃ is It is a fully deuterated methyl group,

However, both X and Z cannot be CH.

The moiety at R ₅ may be substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl or halogen.

Compounds of formula (I) may have the sulfoximine group in the R stereochemical configuration, the S stereochemical configuration, or a mixture of R and S stereochemical configurations.

Compounds of formula (I) contain a deuterated methyl group (-CD ₃ ) on the sulfoximine moiety. However, for other atoms in the compound, atomic masses are not specified. Accordingly, the compounds of the present invention may be isotopically enriched at any position whose atomic mass is not otherwise specified. For example, a compound may have one or more hydrogen atoms replaced with deuterium or tritium. Isotopic substitution or enrichment may occur at carbon, sulfur or phosphorus, or other atoms. For example, and not by way of limitation, a fluorine atom may be ¹⁹ F-rich, a carbon atom may be ¹⁴ C-rich, and a nitrogen atom may be ¹⁵ N-rich. A compound may be isotopically substituted or enriched for a given atom at one or more positions within the compound, or a compound may be isotopically substituted or enriched at all occurrences of a given atom within the compound.

C. Third set of compounds

The compound has the structure of formula (I) or a pharmaceutically acceptable salt thereof.

here:

R ₁ is halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;

R ₂ is selected from the group consisting of aryl, heteroaryl and unsaturated heterocyclyl, where:

Each aryl, heteroaryl and unsaturated heterocyclyl is optionally saturated carbocyclyl containing 5-6 ring members and optionally saturated heterocyclyl containing 5-6 ring members and 1-3 heteroatoms. randomly fused to one selected from the group consisting of;

Each aryl, heteroaryl and unsaturated heterocyclyl is -(CH ₂ ) _n NR ^e C(O)N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ , -(CH ₂ ) _n NR ^e C(O)NR ^e R ^j , -(CH ₂ ) _n NR ^e C(O)OR ^j , -(CH ₂ ) _n NR ^e C(O)R ^j , -(CH ₂ ) _n NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ , -( CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m R ^j , alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl Ponyl, alkyl sulfoxide, alkyl sulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, -C(O)NH ₂ , -C(O)NR ^e R ^j , -C(O)R ^j , C ₁ -C ₄ alkoxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ cycloheteroalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -CN, -CO ₂ H, -CO ₂ R ^j , cyano, -H, halogen, heteroaryl, mono-, di- and trihalo-C ₁ -C ₄ Alkyl, mono-, di- or trihaloalkoxyl, morpholinyl, nitro, O-aryl, -OC(O)N(R ^j ) ₂ , -OC(O)NR ^e R ^j , -OC(O) R ^j , -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ cycloheteroalkyl, -OC ₃ -C ₆ cycloalkyl, -OH, O-heteroaryl, oxazolyl, Oxo, -S(O) ₂ R ^j , -SO ₂ aryl, -SO ₂ C ₁ -C ₆ alkenyl, -SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₂ -C ₆ cycloheteroalkyl, - SO ₂ C ₃ -C ₆ cycloalkyl, SO ₂ heteroaryl, -SO ₂ NH ₂ , -SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ alkyl, -SO ₂ NR ^e C ₂ - C ₆ alkenyl, -SO ₂ NR ^e C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H, -SR ^j , Sulfoximinyl -S(O)(=NR ^a )R ^a , Sulfonimidamide -S(O)(=NR ^a )N(R ^a ) ₂ , Sulfonimidoyl fluoride -S(O)(=NR ^a ) F and sulfondiimine -S (=NR ^a ) ₂ R ^a , wherein each of the alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl substituents is itself optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl) and -N(C ₁ -C ₆ alkyl) ₂ ;

unsaturated heterocyclyl is optionally substituted with R ^k R ^l ;

Each heteroatom in heteroaryl, unsaturated heterocyclyl, and optionally saturated heterocyclyl is independently O, S, or N(R ^h ) _q , each of which may be in its oxidized or non-oxidized state;

R ₃ is -H, cyano, halogen, C ₁ -C ₄ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ -C ₄ alkoxyl, optionally substituted C ₁ -C ₈ alkyl, and C ₃ -C ₈ cycloalkyl optionally substituted with 1-4 fluorine atoms;

Each R ^a is independently halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;

each R ^e is independently -H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl;

Each R ^h is independently -H, or C ₁ -C ₆ alkyl;

Each R ^j is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ cycloheteroalkyl, aryl, or ^heteroaryl , wherein Each of the alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, cyano, and -S(O) ₂ CH ₃ ;

R ^k and R ^l are Together with the atoms to which they are attached, they form a cycloalkyl or cycloheteroalkyl containing 3 to 7 ring members;

E is CH, CF or N;

Q is CH, CF or N;

T is CH, CF or N;

W is CH, CF or N;

X is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

Y is N or N ⁺ O ^- ;

Z is N, N ⁺ O ^- or CH;

Each m is independently 0-2;

Each n is independently 0-4;

Each q is independently 0 or 1.

R ₂ may be optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted unsaturated heterocyclyl.

R ₁ may be H, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl or halocycloalkyl.

R ₃ may be mono-, di-, or trihalo-C ₁ -C ₄ alkyl. R ₃ may be -CF ₃ .

E may be CH, CF or N.

Q may be CH, CF or N.

T may be CH, CF or N.

W may be CH, CF or N.

Its pharmaceutically acceptable salts.

D. Fourth set of compounds

The compound has the structure of formula (I) or a pharmaceutically acceptable salt thereof.

here:

R ₁ is halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;

R ₂ is selected from the group consisting of aryl, heteroaryl and unsaturated heterocyclyl, where:

Each aryl, heteroaryl and unsaturated heterocyclyl is optionally saturated carbocyclyl containing 5-6 ring members and optionally saturated heterocyclyl containing 5-6 ring members and 1-3 heteroatoms. randomly fused to one selected from the group consisting of;

Each aryl, heteroaryl and unsaturated heterocyclyl is -(CH ₂ ) _n NR ^e C(O)N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ , -(CH ₂ ) _n NR ^e C(O)NR ^e R ^j , -(CH ₂ ) _n NR ^e C(O)OR ^j , -(CH ₂ ) _n NR ^e C(O)R ^j , -(CH ₂ ) _n NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ , -( CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m R ^j , alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl Ponyl, alkyl sulfoxide, alkyl sulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, -C(O)NH ₂ , -C(O)NR ^e R ^j , -C(O)R ^j , C ₁ -C ₄ alkoxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ cycloheteroalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -CN, -CO ₂ H, -CO ₂ R ^j , cyano, -H, halogen, heteroaryl, mono-, di- and trihalo-C ₁ -C ₄ Alkyl, mono-, di- or trihaloalkoxyl, morpholinyl, nitro, O-aryl, -OC(O)N(R ^j ) ₂ , -OC(O)NR ^e R ^j , -OC(O) R ^j , -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ cycloheteroalkyl, -OC ₃ -C ₆ cycloalkyl, -OH, O-heteroaryl, oxazolyl, Oxo, -S(O) ₂ R ^j , -SO ₂ aryl, -SO ₂ C ₁ -C ₆ alkenyl, -SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₂ -C ₆ cycloheteroalkyl, - SO ₂ C ₃ -C ₆ cycloalkyl, SO ₂ heteroaryl, -SO ₂ NH ₂ , -SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ alkyl, -SO ₂ NR ^e C ₂ - C ₆ alkenyl, -SO ₂ NR ^e C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H, -SR ^j , Sulfoximinyl -S(O)(=NR ^a )R ^a , Sulfonimidamide -S(O)(=NR ^a )N(R ^a ) ₂ , Sulfonimidoyl fluoride -S(O)(=NR ^a ) F and sulfondiimine -S (=NR ^a ) ₂ R ^a , wherein each of the alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl substituents is itself optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl) and -N(C ₁ -C ₆ alkyl) ₂ ;

unsaturated heterocyclyl is optionally substituted with R ^k R ^l ;

Each heteroatom in heteroaryl, unsaturated heterocyclyl, and optionally saturated heterocyclyl is independently O, S, or N(R ^h ) _q , each of which may be in its oxidized or non-oxidized state;

R ₃ is -H, cyano, halogen, C ₁ -C ₄ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ -C ₄ alkoxyl, optionally substituted C ₁ -C ₈ alkyl, and C ₃ -C ₈ cycloalkyl optionally substituted with 1-4 fluorine atoms;

Each R ^a is independently halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;

each R ^e is independently -H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl;

Each R ^h is independently -H, or C ₁ -C ₆ alkyl;

Each R ^j is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ cycloheteroalkyl, aryl, or ^heteroaryl , wherein Each of the alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, cyano, and -S(O) ₂ CH ₃ ;

R ^k and R ^l are Together with the atoms to which they are attached, they form a cycloalkyl or cycloheteroalkyl containing 3 to 7 ring members;

E is CH or CF;

Q is CH, CF or N;

T is CH, CF or N;

W is CH, CF or N;

X is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,

Y is N or N ⁺ O ^- ;

Z is N or N ⁺ O ^- ,

Each m is independently 0-2;

Each n is independently 0-4;

Each q is independently 0 or 1.

R ₂ may be optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted unsaturated heterocyclyl.

R ₁ may be H, halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl or halocycloalkyl.

R ₃ may be mono-, di-, or trihalo-C ₁ -C ₄ alkyl. R ₃ may be -CF ₃ .

E may be CH, CF or N.

Q may be CH, CF or N.

T may be CH, CF or N.

W may be CH, CF or N.

Its pharmaceutically acceptable salts.

E. Fifth set of compounds

In some embodiments, the subject matter disclosed herein provides compounds of Formula (I) and pharmaceutically acceptable salts thereof.

here:

R ₁ is aryl or heteroaryl, wherein aryl or heteroaryl is unsubstituted or mono-, di-, and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di-, or trihaloalkoxyl, sulfanyl, trifluoro is substituted with one or more groups selected from the group consisting of methylsulfanyl, and arylalkoxyl;

R ₂ is selected from the group consisting of aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted. C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloal. substituted with one or more groups selected from the group consisting of coxyl, arylalkoxyl, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfanonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

R ₃ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ ;

R ₄ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or

R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached.

In some embodiments of compounds of formula (I), R ₁ is phenyl or pyridinyl, wherein phenyl or pyridinyl is unsubstituted, or substituted or unsubstituted C ₁ -C ₈ alkyl, halogen, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 is an integer selected from the group consisting of , 7, and 8), and -S-CF ₃ is substituted with one or more groups selected from the group consisting of;

R ₂ is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, and 1,3- selected from the group consisting of benzothiazolyl, wherein phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, and 1,3-benzothiazolyl is unsubstituted, or unsubstituted or substituted C ₁ -C ₈ alkyl, halogen, cyano, oxo, -OR ₅ (where R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , and -CHF ₂ ), -(CH ₂ ) _q -OH (where q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8), - NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, -C(=O)-R ₈ (where R ₈ is -NR ₆ R ₇ (wherein R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkyl), -S(=O)-R ₉ , -S(=O) ₂ -R ₉ , -S(=O)(=NR ₁₀ )-R ₁₁ , and -N=S(=O)-(R ₁₁ ) ₂ with one or more groups selected from the group consisting of substituted, wherein each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ , or -NR ₆ R ₇ , wherein R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl. and R ₁₀ is H or C ₁ -C ₄ alkyl, R ₁₁ is C ₁ -C ₄ alkyl, provided that when Y is nitrogen and R ₂ is phenyl or pyridyl, R ₈ is -NR ₆ cannot be R ₇ ;

R ₃ is hydrogen, cyano, halogen, -CF ₃ , C ₁ -C ₈ alkoxyl, -O-CH(F) ₂ , substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl , -N ⁺ (=O)-O ^- is selected from the group consisting of;

R ₄ is selected from the group consisting of hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, -CF ₃ , substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ is simultaneously not hydrogen; or

R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached.

In certain embodiments, compounds of Formula (I) include compounds of Formula (II).

here:

R ₂ is selected from the group consisting of aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted. C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloal. substituted with one or more groups selected from the group consisting of coxyl, arylalkoxyl, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfanonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;

R ₃ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ ;

R ₄ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or

R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached;

n is an integer selected from 0, 1, 2, 3, 4 and 5;

Each R ₂₄ is independently mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyanoalkyl. selected from the group consisting of gno, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl.

In some embodiments of compounds of Formula (II), R ₂ is selected from the group consisting of:

here:

m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;

R ₂₅ is H, morpholinyl, oxazolyl, halogen, cyano, -(CH ₂ ) _q -OH (where q is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8) is an integer), -C(=O)-R ₈ where R ₈ is selected from the group consisting of -NR ₆ R ₇ and C ₁ -C ₄ alkyl, where R ₆ and R ₇ are H and C ₁ -C ₄ selected from the group consisting of alkyl), -S(=O)-R ₉ , -S(=O) ₂ -R ₉ , -S(=O)(=NR ₁₀ )-R ₁₁ , and -N=S( =O)-(R ₁₁ ) ₂ (wherein each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ , or -NR ₆ R ₇ , where R ₆ and R ₇ are is selected from the group consisting of H and C ₁ -C ₄ alkyl, R ₁₀ is H or C ₁ -C ₄ alkyl, R ₁₁ is C ₁ -C ₄ alkyl, provided that Y is nitrogen and R ₂ is phenyl or In the case of pyridyl, R ₈ is -NR ₆ cannot be R ₇ );

R ₂₆ is halogen or cyano;

each R ₂₇ is independently selected from the group consisting of H, halogen, C ₁ -C ₈ alkoxyl, cyano, and -NR ₆ R ₇ ;

Each R ₂₈ is independently H or C ₁ -C ₄ alkyl.

In certain embodiments of a compound of Formula (II), the compound is a compound of Formula (II-a).

here:

R ₂ is selected from the group consisting of aryl and heteroaryl, wherein aryl or heteroaryl is unsubstituted or substituted C ₁ -C ₈ alkyl, halogen, cyano, oxo, heterocycloalkyl, -OR ₅ (where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CH ₂ F, and -CHF ₂ ), -(CH ₂ ) _q -OH (where q is 1, 2, 3, 4, 5, is an integer selected from the group consisting of 6, 7, and 8), -NR ₆ R ₇ where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, - C(=O)-R ₈ where R ₈ is -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkyl. selected from the group), -S(=O)-R ₉ , -S(=O) ₂ -R ₉ , -S(=O)(=NR ₁₀ )-R ₁₁ , and -N=S(=O) -(R ₁₁ ) ₂ , where each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ , or -NR ₆ R ₇ , where R ₆ and R ₇ is selected from the group consisting of H and C ₁ -C ₄ alkyl, R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl;

R ₁₂ is selected from the group consisting of halogen, -OR ₂₃ , where R ₂₃ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CH ₂ F, and -CHF ₂ ;

R _12' is selected from the group consisting of H, halogen, -OR ₁₃ , where R ₁₃ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CH ₂ F, and -CHF ₂ .

In certain embodiments of compounds of Formula (II-a), aryl and heteroaryl are selected from the group consisting of phenyl, benzothiazolyl, pyridyl, pyridyl N-oxide, pyridazinyl, and pyrimidinyl.

In certain embodiments of compounds of Formula (II-a), R ₂ is (trifluorosulfonyl)phenyl, 1,2,4-triazolyl, 1,3-benzothiazol-2-yl, 1,3 -Benzothiazol-6-yl, 2-fluoro-5-methylsulfonylphenyl, 2-methoxy-4-pyridyl, 2-methyl-4-pyridyl, 3-(dimethylsulfamoyl)phenyl, 3 -(methylsulfonimidoyl)phenyl, 3-(N,S-dimethylsulfonimidoyl)phenyl, 3-carbamoylphenyl, 3-cyanophenyl, 3-dimethylsulfamoylphenyl, 3-methylsulfinylphenyl, 3-methylsulfonylphenyl, 3-morpholinophenyl, 3-oxazol-5-ylphenyl, 3-pyridyl, 4-cyanophenyl, 4-pyridyl, 6-cyano-3-pyridyl, 6-methyl-3-pyridyl, dimethyl (oxo)-λ6-sulfanylidene] amino] phenyl, phenyl, pyrazolyl, pyridazin-4-yl, pyridazinyl, pyridizin-4-yl, pyridyl, is selected from the group consisting of pyrimidin-4-yl, pyrimidinyl and thiadiazolyl.

In some embodiments, compounds of Formula (I) include compounds of Formula (III).

here:

R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;

R ₂ is

is selected from the group consisting of;

R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ .

In certain embodiments of a compound of Formula (III), the compound is a compound of Formula (III-a).

here:

R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;

R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ .

In certain embodiments of compounds of Formula (IIIa), R ₁ is selected from the group consisting of 2,4-dichlorophenyl, 4-difluoromethoxyphenyl, and 2-chloro-4-methoxyphenyl.

In certain embodiments of the compound of Formula (III), the compound is a compound of Formula (III-b).

here:

R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl) one or more may be substituted;

R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ .

In certain embodiments of the compound of Formula (IIIc), the compound is a compound of Formula (III-c).

here:

R ₁ is one or more of halogen, C ₁ -C ₈ alkyl, phenyl substituted with -OR ₅ , where R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is an integer selected from the group 1, 2, 3, 4, 5, 6, 7, and 8.

In certain embodiments of compounds of Formula (IIIc), R ₁ is 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl. , 2,4-dimethoxyphenyl, 2,4-difluorophenyl, and 3,4-difluorophenyl.

In certain embodiments of a compound of Formula (III), the compound is a compound of Formula (III-d).

here:

R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;

R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ .

In certain embodiments of a compound of Formula (III-d), the compound is a compound of Formula (III-d').

where R ₁ is composed of 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl selected from the group.

In certain embodiments of the compound of Formula (III), the compound is a compound of Formula (III-e).

here:

R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;

R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ .

In certain embodiments of a compound of Formula (III-e), the compound is a compound of Formula (III-e').

where R ₁ is composed of 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl selected from the group.

In certain embodiments of the compound of Formula (III), the compound is a compound of Formula (III-f).

here:

R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;

R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ .

In certain embodiments of a compound of Formula (III-f), the compound is a compound of Formula (III-f').

here:

R ₁ is 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2- It is selected from the group consisting of chloro-4-methoxylphenyl, 3,4-difluorophenyl and 2-chloro-4-fluorophenyl.

In certain embodiments of a compound of Formula (III), the compound is a compound of Formula (III-g).

here:

R ₁ is wherein R _2c is selected from the group consisting of H, C ₁ -C ₄ alkyl, halogen, and C ₁ -C ₄ alkoxyl; R _4c is selected from the group consisting of -OCF ₃ , C ₁ -C ₄ alkoxyl, and halogen;

R ₂ is

is selected from the group consisting of

In certain embodiments of compounds of formula (III-g), R ₁ is

is selected from the group consisting of

In certain embodiments, the compound of Formula (III-g) is selected from the group consisting of:

3-(3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide;

3-(3-(2,4-dimethoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide;

3-(3-(2-chloro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide;

3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-fluoro-2-methoxyphenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(pyridazin-4-yl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-dimethoxyphenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

5-(3-(2,4-dimethoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide;

5-(3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide;

5-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide; and

5-(3-(2-chloro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide.

In some embodiments, compounds of Formula (I) include compounds of Formula (IV).

R ₂ is selected from the group consisting of:

(i) ; where R _2b is selected from the group consisting of H, C ₁ -C ₄ alkyl, and halogen; R ₁₄ is C ₁ -C ₄ alkyl;

(ii) ; where R _5b is selected from the group consisting of -C(=O)-R ₈ , -(CH ₂ ) _n OH, and cyano, where R ₈ is C ₁ -C ₄ alkyl and n is 1, 2, 3 , is an integer selected from 4, 5, 6, 7 and 8;

(iii) , where R _5b' is selected from the group consisting of H, halogen, and C ₁ -C ₄ alkyl;

(iv) , where R _4b is H or halogen;

(v) , where R ₉ is H or C ₁ -C ₄ alkyl; and

(vi) .

In certain embodiments of a compound of Formula (IV), the compound is a compound of Formula (IV-a).

In certain embodiments of compounds of Formula (IV-a), R ₂ is selected from the group consisting of:

.

In certain embodiments of the compound of Formula (IV-a), the compound is selected from the group consisting of:

3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-ethylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonyl-6-methyl-phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonyl-6-fluoro-phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(3-acetylphenyl)-3-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-[3-(hydroxymethyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-[3-cyanophenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(3-pyridyl-N-oxide)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(4-pyridyl-N-oxide)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(2-fluoro-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(2-methyl-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(6-fluoro-3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(6-chloro-3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(1-methyl-2-oxo-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-Chloro-4-fluoro-phenoxy)-N-(2-oxidopyridazin-2-ium-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxyx amides; and

3-(2-Chloro-4-fluoro-phenoxy)-N-pyrimidin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide.

In certain embodiments of a compound of Formula (IV), the compound is a compound of Formula (IV-b).

here:

R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;

R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ ;

R _2b is selected from the group consisting of H, C ₁ -C ₄ alkyl, and halogen; R ₁₄ is C ₁ -C ₄ alkyl;

R ₁₄ is C ₁ -C ₄ alkyl;

R ₁₅ is O or NR ₁₀ , where R ₁₀ is H or C ₁ -C ₄ alkyl.

In certain embodiments of compounds of formula (IV-b), R ₁ is phenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2-propylphenyl, 2-methoxy-4. -Methylphenyl, 2-methoxy-4-chlorophenyl, 2-isopropoxyphenyl, 4-fluoro-2-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-trifluorome Toxyphenyl, 4-trifluoromethoxyphenyl, difluoromethoxyphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-fluorophenyl, 2,5-difluorophenyl, 4-methylphenyl, 3 -Chloro-5-fluorophenyl, 2-isopropylphenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 4-(2,2,2 -Trifluoroethoxy)phenyl, 4-(trifluoromethylsulfanyl)phenyl, 2-dimethylaminophenyl, 2-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 3,4,5-trifluoro Lophenyl, 3,5-dichlorophenyl, 6-trifluoromethyl-3-pyridyl, 1,3-benzothiazol-4-yl, 4-difluoromethoxyphenyl, 2-chloro-4-methoxy It is selected from the group consisting of phenyl, and 2-chlorophenyl.

In certain embodiments of the compound of Formula (IV), the compound is a compound of Formula (IV-c) and pharmaceutically acceptable salts thereof.

here:

R ₁ is ego; here

R _1a , R _1b , R _1c , R _1d , and R _1e are each independently H, C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F , -OCH ₂ CF ₃ , and -NR ₅ R ₆ , where R ₅ and R ₆ are C ₁ -C ₄ alkyl, provided that R _1a , R _1b , R _1c , R _1d , and R At least one of _1e is not H.

In certain embodiments of compounds of formula (IV-c):

(i) R _4a is halogen; R _2a is selected from the group consisting of H, C ₁ -C ₄ alkyl, halogen, and C ₁ -C ₄ alkoxyl; R _3a is H or halogen; R _5a is H or halogen; R _6a is H;

(ii) R _2a and R _4a are each C ₁ -C ₄ alkoxyl;

(iii) R _4a is -OF ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(iv) R _4a is -OCHF ₂ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(v) R _4a is -OCH ₂ F; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(vi) R _4a is -OCH ₂ F ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a , R _5a and R _6a are each H;

(vii) R _3a is halogen; R _2a is H or halogen; R _4a and R _5a are H; R _6a is H or halogen;

(viii) R ₂ is -NR ₅ R ₆ ; R _3a , R _4a , R _5a , and R _6a are each H.

In certain embodiments of compounds of Formula (IV-c), R ₁ is selected from the group consisting of:

.

In certain embodiments of the compound of Formula (IV-c), the compound is selected from the group consisting of:

3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-dichlorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-dimethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -carboxamide;

3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl ) Pyridazine-4-carboxamide;

3-(2-fluoro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ;

3-(2-fluoro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ;

3-(2-fluoro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-methyl-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-methyl-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-methyl-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) Pyridazine-4-carboxamide;

3-(3,4-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(3,4,5-trifluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(3,6-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,3-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-3-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(3-fluoro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ;

3-(3-fluoro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ;

3-(3-fluoro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-chloro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and

3-(2-dimethylaminophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide.

In certain embodiments of the compound of Formula (IV), the compound is a compound of Formula (IV-d) and pharmaceutically acceptable salts thereof.

here:

R ₁ is ego; here

R _1a , R _1b , R _1c , R _1d , and R _1e are each independently H, C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F , -OCH ₂ CF ₃ , and -NR ₅ R ₆ , where R ₅ and R ₆ are C ₁ -C ₄ alkyl, provided that R _1a , R _1b , R _1c , R _1d , and R At least one of _1e is not H.

In certain embodiments of compounds of formula (IV-d):

(i) R _4a is halogen; R _2a is selected from the group consisting of H, C ₁ -C ₄ alkyl, halogen, and C ₁ -C ₄ alkoxyl; R _3a is H or halogen; R _5a is H or halogen; R _6a is H;

(ii) R _2a and R _4a are each C ₁ -C ₄ alkoxyl;

(iii) R _4a is -OF ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(iv) R _4a is -OCHF ₂ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(v) R _4a is -OCH ₂ F; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(vi) R _4a is -OCH ₂ F ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a , R _5a and R _6a are each H;

(vii) R _3a is halogen; R _2a is H or halogen; R _4a and R _5a are H; R _6a is H or halogen;

(viii) R ₂ is -NR ₅ R ₆ ; R _3a , R _4a , R _5a , and R _6a are each H.

In certain embodiments of compounds of Formula (IV-d), R ₁ is selected from the group consisting of:

.

In certain embodiments of the compound of Formula (IV-d), the compound is selected from the group consisting of:

3-(4-fluoro-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-dichlorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-dimethoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-(difluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-(difluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(3-(methylsulfonyl)phenyl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(3-(methylsulfonyl)phenyl)-3-(4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxyx amides;

3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine -4-carboxamide;

3-(2-fluoro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-(difluoromethoxy)-2-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-fluoro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-(difluoromethoxy)-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-(fluoromethoxy)-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine- 4-carboxamide;

3-(3,4-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)-3-(3,4,5-trifluorophenoxy)pyridazine-4-carboxamide;

3-(2,5-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,3-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-3-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(3-fluoro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-(difluoromethoxy)-3-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(3-fluoro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(4-chloro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and

3-(2-(dimethylamino)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide.

In certain embodiments of a compound of Formula (IV), the compound is a compound of Formula (IV-e).

here:

R ₃ is -CF ₂ H, -CH ₂ F, halogen, -OCF ₃ , -OCHF ₂ , -OCFH ₂ , cyclopropyl, branched or straight chain C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyl, sia selected from the group consisting of no, nitro, -SCF ₃ , and SF ₅ ;

R ₄ is selected from the group consisting of H and branched or straight chain C ₁ -C ₄ alkyl.

In certain embodiments of the compound of Formula (IV-e), the compound is selected from the group consisting of:

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(difluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(fluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-chloro-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethoxy)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(difluoromethoxy)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(fluoromethoxy)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-bromo-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-cyclopropyl-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-tert-butyl-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-isopropyl-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-methyl-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5,6-dimethyl-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-methoxy-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-methyl-6-methoxy-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-cyano-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-nitro-pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-((trifluoromethyl)thio)pyridazine-4-carboxamide ; and

3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(pentafluoro-λ ⁶ -sulfanyl)pyridazine-4-car Voxamide.

In certain embodiments of a compound of Formula (IV), the compound is a compound of Formula (IV-f).

here:

R ₁ is ego; here

R _1a , R _1b , R _1c , R _1d , and R _1e are each independently H, C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F , -OCH ₂ CF ₃ , and -NR ₅ R ₆ , where R ₅ and R ₆ are C ₁ -C ₄ alkyl, provided that R _1a , R _1b , R _1c , R _1d , and R At least one of _1e is not H.

In certain embodiments of compounds of formula (IV-f):

(i) R _4a is halogen; R _2a is selected from the group consisting of H, C ₁ -C ₄ alkyl, halogen, and C ₁ -C ₄ alkoxyl; R _3a is H or halogen; R _5a is H or halogen; R _6a is H;

(ii) R _2a is C ₁ -C ₄ alkoxyl and R _4a is selected from the group consisting of C ₁ -C ₄ alkoxyl and halogen;

(iii) R _4a is -OF ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(iv) R _4a is -OCHF ₂ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(v) R _4a is -OCH ₂ F; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;

(vi) R _4a is -OCH ₂ F ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a , R _5a and R _6a are each H;

(vii) R _3a is halogen; R _2a is H or halogen; R _4a and R _5a are H; R _6a is H or halogen;

(viii) R ₂ is -NR ₅ R ₆ ; R _3a , R _4a , R _5a , and R _6a are each H.

In certain embodiments of compounds of Formula (IV-f), R ₁ is selected from the group consisting of:

.

In certain embodiments of the compound of Formula (IV), the compound is selected from the group consisting of:

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-dichlorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,4-dimethoxyphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide;

3-(2-chloro-4-(difluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide;

3-(2-chloro-4-(fluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-car boxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide hydrochloride ;

3-(4-(difluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoromethyl)pyridazine -4-carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoro Romethyl)pyridazine-4-carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4 -carboxamide;

3-(4-(difluoromethoxy)-2-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4- carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4- carboxamide;

3-(4-(difluoromethoxy)-2-methylphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(fluoromethoxy)-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-car boxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoro methyl)pyridazine-4-carboxamide;

3-(3,4-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)-3-(3,4,5-trifluorophenoxy)pyridazine-4-carboxamide ;

3-(2,5-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2,3-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-chloro-3-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(3-fluoro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4 -Carboxamide;

3-(4-(difluoromethoxy)-3-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -carboxamide;

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(3-fluoro-4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4- carboxamide;

3-(4-chloro-2-methoxyphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;

3-(2-(dimethylamino)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and

N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide .

In certain embodiments of a compound of Formula (IV), the compound is a compound of Formula (IV-g).

here:

R ₁ is selected from the group consisting of 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl;

R ₂₀ is C ₁ -C ₄ alkyl;

R ₂₁ is H or C ₁ -C ₄ alkyl.

In another embodiment, a subject disclosed herein is a subject suffering from a condition, disease or disorder associated with increased Na _v 1.8 activity or expression, comprising the use of a compound of formula (I-IV) in the manufacture of a medicament for the treatment of such disorder. Provides a purpose.

F. Composition

The present invention provides pharmaceutical compositions containing compounds of the invention, such as those described above. Pharmaceutical compositions may be in forms suitable for oral use, such as tablets, troches, lozenges, quick-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may be enriched with sweeteners, flavoring agents, colorants and preservatives to provide pharmaceutically elegant and palatable preparations. It may contain one or more agents selected from. Tablets contain the compound mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agents such as corn starch or alginic acid; There may be binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known techniques to delay disintegration in the stomach and poor absorption from the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time delay substances such as glyceryl monostearate or glyceryl distearate may be used. They also include U.S. Patent Nos. 4,256,108; the contents of which are incorporated herein by reference; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release. Preparation and administration of the compounds are discussed in U.S. Pat. No. 6,214,841 and U.S. Publication No. 2003/0232877, the contents of which are incorporated herein by reference.

Preparations for oral use can also be prepared as hard gelatin capsules in which the compound is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or where the compound is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. It can be provided as a soft gelatin capsule mixed with.

Alternative oral formulations where control of gastrointestinal hydrolysis of the compound is sought can be achieved using controlled-release formulations in which the compound of the invention is encapsulated in an enteric coating.

Aqueous suspensions may contain the compounds admixed with excipients suitable for the manufacture of aqueous suspensions. These excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; Dispersants or wetting agents, such as naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. For example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene and partial esters derived from fatty acids and hexitol anhydrides, such as polyoxy It is ethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives, such as ethyl, or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin. You can.

Oily suspensions can be formulated by suspending the compound in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions may contain thickening agents, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those described above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by the addition of antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of aqueous suspensions by addition of water provide compounds mixed with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, and sweetening, flavoring and coloring agents, for example, may also be present.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin or mixtures thereof. Suitable emulsifiers include naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phosphatides, such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydride, such as sorbitan. monooleates and condensation products of such partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. These preparations may also contain emollients, preservatives, and flavoring and/or coloring agents. Pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic mono- or di-glycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

In certain embodiments, the formulation is a sustained release formulation. In certain embodiments, the formulation is not a sustained release formulation. In certain embodiments, the formulation is not injectable. In certain embodiments, the formulation does not contain particles with a D50 (volume weighted median diameter) less than 10 micrometers. In certain embodiments, the formulation does not contain polymeric surface stabilizers. In certain embodiments, the formulation is not an aqueous suspension.

Compositions can be formulated for administration by a specific mechanism. Compositions may be formulated for oral, intravenous, enteral, parenteral, dermal, buccal, topical, nasal, or pulmonary administration. The compositions may be formulated for administration by injection or on an implantable medical device (eg, a stent or drug-eluting stent or balloon equivalent).

The composition may be formulated for a single daily dosage. The composition may be formulated for multiple daily doses, for example, 2, 3, 4, 5, 6 or more daily doses.

In another aspect, the disclosure provides pharmaceutical compositions comprising one or more compounds of the invention, alone or in combination with one or more additional therapeutic agents, in admixture with pharmaceutically acceptable excipients. Those skilled in the art will recognize that the pharmaceutical compositions include pharmaceutically acceptable salts of the compounds described above. Pharmaceutically acceptable salts are generally well known to those skilled in the art and include salts of the active compounds prepared using relatively non-toxic acids or bases depending on the specific substituent moieties found on the compounds described herein. do. When compounds of the present disclosure contain relatively acidic functional groups, base addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent or by ion exchange. may be, where one type of basic counterion (base) replaces another in the ionic complex. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts.

When compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, neat or in a suitable inert solvent or by ion exchange, Here, one acidic counterion (acid) replaces another in an ionic complex. Examples of pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrogensulfuric acid, iodination. those derived from hydronic acid or phosphorous acid, etc., as well as relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid. , p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids, such as arginate, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19]. Certain specific compounds of the present disclosure contain both basic and acidic functional groups that allow the compounds to be converted to base or acid addition salts.

Accordingly, pharmaceutically acceptable salts suitable for use with the subject matter disclosed herein include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsyl. erythate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydrochloride Bromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, maleate, maleate, mandelate, mesylate, mucate, naphsylate, nitrate, pamoate. (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate or theoclate. Other pharmaceutically acceptable salts can be found, for example, in Remington: The Science and Practice of Pharmacy ( ^20th ed.) Lippincott, Williams & Wilkins (2000).

Depending on the particular condition being treated, these agents may be formulated in liquid or solid dosage forms and administered systemically or topically. The agent may be delivered in a timed- or sustained-slow release form, for example, as known to those skilled in the art. Formulation and administration techniques can be found in Remington: The Science and Practice of Pharmacy ( ^20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal, or enteral administration; Parenteral delivery, such as intramuscular, subcutaneous, intramedullary injection, as well as intrathecal, directly intracerebroventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular. This may include injection or other delivery methods.

For injection, the agents of the present disclosure can be formulated and diluted in aqueous solutions, such as physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, a penetrating agent suitable for the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art.

The use of pharmaceutically acceptable inert carriers in the practice of this disclosure to formulate the compounds disclosed herein in dosages suitable for systemic administration is within the scope of this disclosure. With appropriate selection of carrier and appropriate manufacturing practices, compositions of the present disclosure, especially formulated as solutions, can be administered parenterally, such as by intravenous injection. Compounds can be readily formulated in dosages suitable for oral administration using pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc. for oral intake by the subject to be treated (e.g., a patient).

For nasal or inhalation delivery, the agents of the present disclosure can also be formulated by methods known to those skilled in the art, for example, in solubilizing, diluting or dispersing agents such as saline; Preservatives such as benzyl alcohol; Absorption enhancers; and fluorocarbons, but are not limited thereto.

Pharmaceutical compositions suitable for use in the present disclosure include compositions containing the active ingredients in amounts effective to achieve their intended purpose. Determination of an effective amount is well within the ability of one of ordinary skill in the art, especially in light of the detailed disclosure provided herein. In general, compounds according to the present disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, doses of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, the bioavailability of the compound(s), the adsorption, distribution, metabolism and excretion (ADME) toxicity of the compound(s), and the responsible Significance will vary depending on preference and experience.

In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers, including excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.

Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; Cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose (CMC) and/or polyvinylpyrroli It's money (PVP: Povidone). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or salts thereof such as sodium alginate may be added.

Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvents. May contain mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starch, and/or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin or liquid polyethylene glycol (PEG). Additionally, stabilizers may be added.

G. How to treat the condition

The present invention provides methods of treating a condition in a subject using the compounds of the invention. The method is useful for treating any condition associated with abnormalities, e.g., increased activity, of voltage-gated Na _V 1.8 sodium channels. Conditions associated with increased activity of Na _V 1.8 and the uses of Na _V 1.8 to treat such conditions are known in the art, for example in International Patent Publication No. WO, the contents of each of which are incorporated herein by reference. It is described in 2020/014243, WO 2020/014246, and WO 2020/092187.

For example and without limitation, conditions include abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute pruritus, acute pain, acute pain from major trauma/injury, airway hyperresponsiveness, allergic dermatitis, allergies, ankylosing spondylitis, Asthma, atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemistry. Therapy-induced peripheral neuropathy, cholestasis, chronic cough, chronic pruritus, chronic back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndrome, additional Persistent unilateral facial pain with paroxysms, contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, associated with highly active antiretroviral therapy (HAART) Distal sensory polyneuropathy (DSP), Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, epilepsy, erythroderma, Fabry disease, facet joint syndrome, failed spinal surgery syndrome, familial hemiplegic migraine, fibromyalgia, Glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary erythroderma, irritable bowel syndrome, irritable bowel syndrome, itching, juvenile idiopathic arthritis, mastocytosis, adenoid hyperostosis, migraine , multiple sclerosis, musculoskeletal injury, myofascial orofacial pain, post-ischemic neurodegeneration, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral cavity. Mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, congenital onychohypertrophy, pain, pain due to cancer, pain due to chemotherapy, pain due to diabetes, pain syndrome, painful joint arthroplasty, pancreatitis, Parkinson's disease, paroxysmal pain. Extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, postoperative pain, stroke. Post-operative pain, post-operative pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, pre-operative pain, pruritus, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal Colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, short pain, subacute cough, temporomandibular joint disorder. , tension headaches, trigeminal neuralgia, vascular leg ulcers, vulvodynia, or whiplash-related disorders.

A method of treating a condition in a subject may include providing the subject with a composition of the invention. The composition may be provided to the subject by any suitable route or mode of administration. For example and without limitation, the compositions can be administered bucally, dermally, enterally, intraarterially, intramuscularly, intraocularly, intravenously, nasally, orally, parenterally, pulmonaryly, rectally, subcutaneously, topically. , transdermally, by injection, or with or on an implantable medical device.

Compositions may be provided according to an administration regimen. The dosing regimen may include one or more of dosage, frequency of administration, and duration.

Doses may be given at any suitable interval. For example and not by way of limitation, dosages include 1 time per day, 2 times per day, 3 times per day, 4 times per day, 5 times per day, 6 times per day, 8 times per day, once every 48 hours. , once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every 2 days, 3 It may be given once per day, once every 4 days, once every 5 days, once per week, twice per week, three times per week, four times per week, or five times per week.

The dosage may be provided in a single dosage, i.e. the dosage may be provided as a single tablet, capsule, pill, etc. Alternatively, the dose may be given in divided doses, i.e., the dose may be given as multiple tablets, capsules, pills, etc.

Administration may continue for a defined period of time. For example and without limitation, the dosage may be at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 4 months, at least 5 months, It may be provided for at least 6 months, at least 8 months, at least 10 months, at least 12 months or longer.

In some embodiments, subjects disclosed herein provide methods of modulating the Na _v 1.8 sodium ion channel, comprising administering to a subject in need of modulation _a modulating effective amount of a compound disclosed herein. do.

In another embodiment, the subject matter disclosed herein provides a method of inhibiting Na _v 1.8 comprising administering to a subject in need of inhibition of Na _v 1.8 an inhibitory effective amount of a compound disclosed herein.

As used herein, the term "inhibit" and its grammatical derivatives refer to compounds disclosed herein that block, partially block, interfere with, reduce or reduce the activity or expression of Na _v 1.8 in a subject, e.g. refers to the abilities of compounds of formula (I-IV) disclosed in Accordingly, those skilled in the art will understand that the term "inhibit" refers to a complete and/or partial reduction in the function of a channel, e.g., a reduction of at least 10%, in some embodiments, at least 20%, 30%, It will be appreciated that this encompasses reductions of 50%, 75%, 95%, 98%, and 100%.

In certain embodiments, the subject matter disclosed herein provides methods of treating a condition, disease, or disorder associated with increased Na _v 1.8 activity or expression. In more specific embodiments, the condition, disease or disorder associated with increased Na _v 1.8 activity or expression is pain, particularly inflammatory, visceral and neuropathic pain, neurological disorders, especially multiple sclerosis, autism, especially Pitt-Hopkins syndrome, and psychiatric disorders. diseases, and combinations thereof, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the disease or condition is neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, postoperative pain, labor pain, labor pain, neurogenic bladder, ulcerative colitis. , chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve damage, or a combination thereof.

In other embodiments, the disease or condition includes pain associated with HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), and Referred pain, amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia gravis syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, Rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, diseases related to sodium channel toxicity, familial erythrodynia, primary erythrodynia, familial proctalgia, cancer, epilepsy, partial and generalized tonic seizures, restless legs syndrome. , arrhythmia, fibromyalgia, neuroprotection under ischemic conditions induced by stroke or neurological trauma, tach-arrhythmias, atrial fibrillation and ventricular fibrillation.

In some embodiments, the disease or condition is Fitz-Hopkins Syndrome (PTHS).

The subject matter disclosed herein also includes the use of a compound disclosed herein in the manufacture of a medicament for the treatment of a condition, disease or disorder associated with increased Na _v 1.8 activity or expression in a subject suffering from such disorder.

Although it should be understood that the methods described herein are effective for all vertebrate species intended to be encompassed by the term "subject," in many embodiments thereof the "subject" treated by the methods disclosed herein is preferably a human subject. am. Accordingly, “subject” may include human subjects for medical purposes, such as treatment of a pre-existing condition or disease or prophylactic treatment to prevent the development of a condition or disease, or animal subjects for medical, veterinary or developmental purposes. You can. Suitable animal subjects include primates, such as humans, monkeys, apes, etc.; cattle, such as cattle, oxen, etc.; Sheep, for example sheep, etc.; goats, such as goats, etc.; Pigs, such as pigs, pigs, etc.; Horses, such as horses, donkeys, zebras, etc.; Cats, including wild and domestic cats; a dog, for example a dog; Lagomorphs, rabbits, etc.; and mammals, including but not limited to rodents, such as mice, rats, etc. The animal may be a transgenic animal. In some embodiments, the subject is a human, including but not limited to fetal, neonatal, infant, pediatric, and adult subjects. Additionally, “subject” may include a patient suffering from or suspected of suffering from a condition or disease. Accordingly, the terms “subject” and “patient” are used interchangeably herein. The term “subject” also refers to an organism, tissue, cell, or collection of cells from a subject.

Generally, an “effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of agent or device may vary depending on factors such as the desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue, etc.

The term “combination” is used in its broadest sense and refers to a subject receiving at least two agents, more particularly a compound disclosed herein and at least one analgesic agent; and, optionally, receiving one or more analgesics. More particularly, the term “in combination” refers to the combined administration of two (or more) active agents, for example, for the treatment of a single disease state. The active agents used herein may be combined and administered in a single dosage form, may be administered simultaneously as separate dosage forms, or may be administered as separate dosage forms administered alternately or sequentially on the same or separate days. In one embodiment of the subject matter disclosed herein, the active agents are combined and administered in a single dosage form. In another embodiment, the active agent is administered in separate dosage forms (e.g., where it is desirable to vary the amount of one but not the other). Single dosage forms may include additional active agents for the treatment of disease states.

Additionally, the compounds described herein can be administered alone or in combination with one or more analgesics, either alone or in combination with an adjuvant that enhances the stability of the compounds described herein, and in certain embodiments, pharmaceutical compositions containing them. can facilitate administration, provide increased dissolution or dispersion, increase inhibitory activity, provide adjuvant therapy, etc., including other active ingredients. Advantageously, such combination therapy utilizes lower doses of conventional therapeutic agents and thus avoids the possible toxicity and adverse side effects that would occur if these agents were used as monotherapies.

The timing of administration of the compounds disclosed herein and at least one additional therapeutic agent may vary as long as the beneficial effects of the combination of these agents are achieved. Accordingly, the phrase “in combination with” refers to administering a compound disclosed herein and at least one additional therapeutic agent simultaneously, sequentially, or in a combination thereof. Accordingly, a subject administered a combination of a compound disclosed herein and at least one additional therapeutic agent may receive the compound disclosed herein and at least one additional therapeutic agent as long as the effect of the combination of both agents is achieved in the subject. You may receive the compounds from simultaneously (i.e. simultaneously) or at different times (i.e. sequentially, in any order, on the same day or on different days).

When administered sequentially, the agents may be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or more of each other. In other embodiments, sequentially administered agents may be administered within 1, 5, 10, 15, 20 days or more of each other. When a compound selected from the compounds disclosed herein and at least one additional therapeutic agent are administered simultaneously, they will each be administered to the subject as separate pharmaceutical compositions comprising a compound selected from the compounds disclosed herein or at least one additional therapeutic agent. Alternatively, they can be administered to the subject as a single pharmaceutical composition containing both agents.

When administered in combination, the effective concentration of each agent to elicit a particular biological response may be less than the effective concentration of each agent when administered alone, thereby reducing the dose that would be required if the agents were administered as a single agent. Compared to , it is possible to reduce the dose of one or more of the agents. The effects of multiple agents may, but need not, be additive or synergistic. The agent may be administered multiple times.

In some embodiments, when administered in combination, two or more agents may have a synergistic effect. As used herein, the terms “synergistic,” “synergistic,” “synergistically,” and their derivatives, such as “synergistic effect,” or “synergistic combination” or “synergistic composition,” are used herein. refers to a situation where the biological activity of a combination of a compound selected from the compounds disclosed in and at least one additional therapeutic agent is greater than the sum of the biological activities of the individual agents when administered individually.

Synergy is generally described in [F. By the method described in C. Kull et al., Applied Microbiology 9, 538 (1961), the "synergism index (SI)" can be determined from the ratio determined by:

Q _a /Q _A + Q _b /Q _B = Synergy Index (SI)

here:

Q _A is the concentration of component A acting alone that produces the endpoint with respect to component A;

Q _a is the concentration of component A in the mixture that produces the endpoint;

Q _B is the concentration of component B acting alone that produces the endpoint with respect to component B;

Q _b is the concentration of component B in the mixture that produces the endpoint.

In general, if the sum of Q _a /Q _A and Q _b /Q _B is greater than 1, antagonism is indicated. If the sum is 1, an additive effect occurs. If the sum is less than 1, synergy is demonstrated. The lower the SI, the greater the synergy exhibited by that particular mixture. Accordingly, a “synergistic combination” has a higher activity than might be expected based on the observed activity of the individual components when used alone. Additionally, a “synergistically effective amount” of an ingredient refers to the amount of ingredient necessary to produce a synergistic effect, e.g., in another therapeutic agent present in the composition.

More particularly, in some embodiments, the methods disclosed herein comprise co-administering to a subject a compound selected from the compounds disclosed herein and/or pharmaceutically acceptable salts thereof with one or more compounds selected from the group consisting of: Includes:

Nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, keto Profen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozine, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, and zomepirac; Opioid analgesics, including but not limited to morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxy fen, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and pentazocine; Barbiturates, including but not limited to amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, and talbutal. , thiamylal, and thiopental; benzodiazapines, including but not limited to chlordiazepoxide, chlorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, and triazolam; histamine H ₁ antagonists, Such as, but not limited to, diphenhydramine, pyrylamine, promethazine, chlorpheniramine, and chlorcyclizine;

Sedatives such as, but not limited to, glutethimide, meprobamate, methaqualone, and dichloralphenazone; Skeletal muscle relaxants such as, but not limited to, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, and orprenadine;

NMDA receptor antagonists, such as but not limited to dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrophane ((+)-3-hydroxy-N-methylmorphinan) finan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), morphine, and combination preparations of dextromethorphan), topiramate, neramexane or perzinfotel such as NR2B antagonists such as ifenprodil, traxoprodil, and (-)-(R)-6-{2- [4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone; transient receptor potential ion channel antagonist; α-adrenergic, including but not limited to doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido -1, 2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline; Tricyclic antidepressants such as, but not limited to, desipramine, imipramine, amitriptyline, and nortriptyline; Anticonvulsants such as, but not limited to, carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), and valproate; Tachykinin antagonists, especially NK-3, NK-2 or NK-1 antagonists, such as but not limited to (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9 ,10,11-Tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazosino[2,1-g][1,7]-naphthyridine-6-13- Di-one (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4- fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, ranepitant, Dapitant, and 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S); Muscarinic antagonists such as, but not limited to, oxybutynin, tolterodine, propiverine, tropcium chloride, darifenacin, solifenacin, temiverine, and ipratropium; Cyclooxygenase-2 selective (COX-2) inhibitors such as, but not limited to, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, and lumiracoxib; Coal-tar analgesics such as, but not limited to, paracetamol;

Neuroleptics, including but not limited to droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetia Pin, sertindol, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, racloprid, zotepine, bifeprunox, asenapine, lurasidone, amisulprid, balaperidone, palindore, eplibanserin, oxanetant, rimonabant, meclinantant, Miraxion®, and sarizotan; vanilloid receptor agonists such as, but not limited to, resinferatoxin or cibamide);

vanilloid receptor antagonists such as, but not limited to, capsazepine or GRC-15300);

β-adrenergic, including but not limited to propranolol; Local anesthetics, including but not limited to mexiletine; Corticosteroids, including but not limited to dexamethasone and prednisone; 5-HT receptor agonists or antagonists, especially 5-HT _1B/1D agonists, such as but not limited to eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

5-HT ₂ A receptor antagonists, such as but not limited to R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine Methanol (MDL-100907), eplibanserin, ketanserin, and pimavanserin; Cholinergic (nicotinic acid) analgesics such as, but not limited to, ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), and nicotine; α ₂ δ ligands such as, but not limited to, gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin, enacarbyl (Horizant®), pregabalin (Lyrica) )®), 3-methyl gabapentin, (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S ,5R)-3-Aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(aminomethyl) Bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1- (1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3 -Aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R, 5R)-3-Amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid; cannabinoid receptor ligands, including but not limited to cannabidiol, KHK-6188; Metabotropic glutamate subtype 1 receptor antagonist;

Serotonin reuptake inhibitors, including but not limited to sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolism Water desmethylcitalopram, escitalopram, d,l-fenfluramine, pemoxetine, ipoxetine, cyanodothiepine, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone; noradrenaline (Norepinephrine) reuptake inhibitors such as, but not limited to, maprotiline, rofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybut Proprion, nomifensine and biloxazine (Vivalan®), especially selective noradrenaline reuptake inhibitors such as reboxetine, especially (S,S)-reboxetine; Dual serotonin-noradrenaline reuptake inhibitors, including but not limited to venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®) ), milnacipran and imipramine; Rho kinase inhibitors; inducible nitric oxide synthase (iNOS) inhibitors such as, but not limited to, S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l- iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S, 5Z)-2-Amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1- (5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4- [[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thia Zolyl) butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl ]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462, and

guanidinoethyl disulfide; Acetylcholinesterase inhibitors such as but not limited to donepezil;

Prostaglandin E ₂ subtype 4 antagonists, such as but not limited to N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl) phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide, and 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl ]carbonyl}amino)ethyl]benzoic acid; Leukotriene B4 antagonists, such as but not limited to 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2- (2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057), and DPC-11870; 5-lipoxygenase inhibitors such as, but not limited to, zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl] )phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), and 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504) ;

Sodium channel blockers such as, but not limited to, lidocaine, lidocaine plus tetracaine cream (ZRS-201), and eslicarbazepine acetate; 5-HT ₃ antagonists such as but not limited to ondansetron; N-methyl-D-aspartate receptor antagonists; Voltage-gated calcium channel blockers (e.g., N-type and T-type) such as, but not limited to, Zicontide, Z-160, (R)-2-( 4-cyclopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide;

KCNQ openers (e.g., KCNQ2/3 (K _v 7.2/3)); TPRV 1 receptor agonists such as, but not limited to, capsaicin (Neuroges®, Qutenza®); and pharmaceutically acceptable salts and solvates thereof; Nicotinic acid receptor antagonists such as but not limited to varenicline; Nerve growth factor antagonists, such as but not limited to tanezumab; Endopeptidase stimulators, such as but not limited to senrobotase; Angiotensin II antagonists, such as but not limited to EMA-401; Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®); PDE5 inhibitors, such as but not limited to 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro -7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-( 3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-Ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f] [1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3- Azetidinyl)-2,6-di-hydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3 -Ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy -5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4, 3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl] -N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4, 3-d]pyrimidin-5-yl)-- N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

Na _V 1.7 blockers such as but not limited to XEN-402, WO2012/106499; WO2012/112743; disclosed in WO2012/125613, WO2012/116440, WO2011026240, US Patent No. 8,883,840, or 8,466,188, or PCT/US2013/21535 (the entire contents of each application are incorporated herein by reference); and

Na _V 1.7 blockers, such as but not limited to (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl)-(4 -Isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy] Benzoyl]-2-,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]-ethanone, [8- Fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1-,2-a]pyrazine-1,4'-piperidin]-1'-yl] -(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy] Propan-2-ol, (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a] pyrazine-1,4'-piperidin]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1 ,2-a]pyrazine-1,4'-piperidin]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy -3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidin]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3, 4-dihydropyrrolo-[1,2-a]pyrazine-1,4'-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3- Methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl ]Methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3 ,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-( 5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3, 3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperi din]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4- Dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl- 6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 2,2,2 -Trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine- 1,4'-piperidin]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl) Benzoyl]spiro[3, 4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2,2-trifluoro-ethanone, [ 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl ]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6 -methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl] Ethanone, 1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1 ,4'-piperidin]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoro Romethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, [2-methyl-6-(1- Methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]-pyrazine-1,4'-piperidin]-1'-yl]-[4-(3,3, 3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl] Benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[34-dihydropyrrolo[1 ,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone.

In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, with or without a pharmaceutically acceptable carrier, with a second agent selected from the group consisting of acetaminophen, NSAIDs, opioid analgesics, and combinations thereof. Including administration in combination with therapeutic agents.

In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, in combination with one or more additional therapeutic agents for treating pain, with or without a pharmaceutically acceptable carrier. Includes. In one embodiment, the additional therapeutic agent is selected from the group consisting of acetaminophen, NSAIDs (such as aspirin, ibuprofen, and naproxen), and opioid analgesics. In another embodiment, the additional therapeutic agent is acetaminophen. In another embodiment, the additional therapeutic agent is an NSAID. In another embodiment, the additional therapeutic agent is an opioid analgesic.

Brief description of the drawing

Figure 1: Illustration of Protocol 1 for performing the Na _v 1.8 inhibition assay.

V. Examples

The following examples are included to provide guidance to those skilled in the art for practicing representative embodiments of the subject matter disclosed herein. In light of the general level of the present disclosure and the related art, those skilled in the art will appreciate that the following examples are intended to be illustrative only and that numerous changes, modifications and alterations may be made without departing from the scope of the subject matter disclosed herein. You can recognize that it exists. The following synthetic description and specific examples are for illustrative purposes only and should not be construed as limiting in any way the preparation of the compounds of the present disclosure by other methods.

A. Examples of the first set of compounds

Example 1

Methods for preparing the compounds of the invention and the intermediates used in their synthesis are provided in the general synthetic schemes and specific synthetic procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise indicated. Alternatively, their preparation is easy and is known to those skilled in the art or is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “Dry” glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise indicated.

All reactions were performed under positive pressure of dry nitrogen or dry argon in flame-dried or oven-dried glassware and magnetically stirred unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise indicated. Yield was not optimized. Chemical names were generated using ChemDraw Professional 19.1, available from PerkinElmer or ChemAxon.

The reaction was monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD MILLIPORE™. Purification was performed with a CombiFlash NextGen 300 automated flash chromatography system or using one of the preparative HPLC methods mentioned below. Analytical data was collected using one of the analytical methods described below.

Example 2

Purification Method 1 (P1): Acidic Initial Method

Purification (METCR/Prep004) (P1) LC was performed using a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature) for 0.55 min in an injection volume of 1500 μL at a flow rate of 40 mL/min. A gradient of 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 10 - 95% B over 13.89 minutes and held for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 2 (P2): Acid Standard Method

Purification (METCR/Prep001) (P2) LC was performed using a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature) for 0.55 min in an injection volume of 1500 μL at a flow rate of 40 mL/min. A gradient of 30% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 30 - 95% B over 10.45 minutes and held for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.21 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 3 (P3): Basic Initial Method

Purification (METCR/Prep002) (P3) LC was performed using a Waters 10% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) followed by a gradient of 10 - 95% B over 13.89 minutes and held for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 4 (P4): Basic Standard Method

Purification (METCR/Prep003) (P4) LC was performed using a Waters A gradient of 30% B over 10.45 minutes (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) followed by a gradient of 30 - 95% B over 10.45 minutes and held for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.21 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

LCMC for analysis were collected using one of the following methods:

Method 1 (M1): Acid IPC Method (METCR1410 - MS17, MS18, MS19)

Analysis (MET/CR/1410) (M1) HPLC-MS was performed using a Kinetex Core Shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40°C) with 3 μL of A gradient of 5 - 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.1 min was performed in the injection volume over 1.2 min. A second gradient of 100 - 5% B was then applied over 0.01 minutes and held for 0.39 minutes. UV spectra were recorded at 215 nm using SPD-M20A PDA detector, spectral range: 210 - 400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 3 (M3): Basic IPC method (MET-uPLC-AB-2005 - MS16, MSQ5)

Analysis (MET/uPLC/AB2005) (M14) uHPLC-MS was performed using a Waters uPLC® BEHTM C18 column (2.1 mm x 30 mm, 1.7 μm; temperature 40°C), 1 μL injection at a flow rate of 1.0 mL/min. A gradient of 1 - 100% B in volume over 1.1 minutes (A = 2 mM ammonium bicarbonate in water, buffered to pH 10; B = acetonitrile) followed by 100% B over 0.25 minutes was performed. A second gradient of 100 - 1% B was then applied over 0.05 minutes and held for 0.4 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm. Mass spectra were obtained using a Waters Quatro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MathLynx and OpenLynx software.

Method 4 (M4): Acidic Final Analytical Method (METCR-uPLC-AB101 - MSQ1, MSQ2, MSQ4)

Analysis (MET/uPLC/AB101) (M4) uHPLC-MS was performed using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μm; temperature: 40°C) at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5.3 min (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.5 min was performed in an injection volume of 1 μL. A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm, and ELS data were collected on a Waters Acquity ELS detector when reported. Mass spectra were obtained using Waters SQD or Waters Acquity QDA. Data were integrated and reported using Waters MathLynx and OpenLynx software.

Method 5 (M5): Acidic Final Analytical Method (METCR1416 - MS18, MS19)

Analysis (MET/CR/1416) (M5) HPLC-MS was performed using a Waters Atlantis dC18 column (2.1 mm x 100 mm, 3 μm; temperature: 40°C) with an injection volume of 3 μL at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5 minutes (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.4 minutes was performed. A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.58 minutes. UV spectra were recorded at 215 nm using SPD-M20A PDA detector, spectral range: 210 - 400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 6 (M6): Basic Final Analysis Method (MET-uPLC-AB105 - MS16, MSQ5)

Analysis (MET/uHPLC/AB105) (M8) uHPLC-MS was performed using a Waters uPLC® BEHTM C18 column (2.1 mm x 100 mm, 1.7 μm column; temperature: 40°C) at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5.3 minutes (A = 2 mM ammonium bicarbonate in water, buffered to pH 10; B = acetonitrile) followed by 100% B over 0.5 minutes was performed at an injection volume of . A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm. Mass spectra were obtained using a Waters Quatro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MathLynx and OpenLynx software.

Method 7:

Mass spectrometry data was collected using a Waters Acquity H-Class ultra high pressure liquid chromatograph coupled to a Waters Acquity TQD mass spectrometer. Samples were separated and resolved using an Acquity UPLC BEH C18 column (2.1 x 50 mm). Compounds were eluted from the column using a 10 min linear solvent gradient: 0-0.5 min, 5% B; 0.5 - 6.5 min, 100% B, 6.5-7.5 min; 100% B, 7.5-8.1 min; 5% B, 8.1-10 min; 5% B. Solvent flow rate is 0.45 mL per minute. Solvent A was water and solvent B was acetonitrile. Mass spectra were collected in positive or negative ion mode with the following parameters: 2.5 kV capillary voltage; 25 V sampling cone voltage; 140°C source temperature; 400°C desolvation temperature; Nitrogen desolvation at 800 L/hr.

Unless otherwise stated, ¹ H nuclear magnetic resonance spectroscopy (NMR) spectra were obtained from a Bruker™ 300 MHz on a Bruker Avance III HD 500 MHz spectrometer or a Bruker Avance III HD 400 MHz spectrometer. or recorded on 500 MHz, 400 MHz or 250 MHz. Chemical shifts δ are quoted in parts per million (ppm) relative to TMS and are calibrated using residual non-deuterated solvent as an internal reference. The following abbreviations are used to indicate multiplicity and general assignment: s (singlet), d (doublet), t (triple), q (quartet), dd (doublet of a doublet), ddd (doublet of a doublet) doublet), dt (doublet of triplets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triplet of doublets), qd (quartet of doublets) ), app. (obvious) and br. (broadness). The coupling constant J is rounded to the nearest 0.1 Hz.

Example 3

The purification method is as follows:

Purification Method 1 (P1): Acidic Initial Method

Purification (METCR/Prep004) (P1) LC was performed using a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature) for 0.55 min in an injection volume of 1500 μL at a flow rate of 40 mL/min. A gradient of 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 10 - 95% B over 13.89 minutes and held for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 2 (P2): Acid Standard Method

Purification (METCR/Prep001) (P2) LC was performed using a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature) for 0.55 min in an injection volume of 1500 μL at a flow rate of 40 mL/min. A gradient of 30% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 30 - 95% B over 10.45 minutes and held for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.21 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 3 (P3): Basic Initial Method

Purification (METCR/Prep002) (P3) LC was performed using a Waters 10% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) followed by a gradient of 10 - 95% B over 13.89 minutes and held for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 4 (P4): Basic Standard Method

Purification (METCR/Prep003) (P4) LC was performed using a Waters A gradient of 30% B over 10.45 minutes (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) followed by a gradient of 30 - 95% B over 10.45 minutes and held for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.21 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Example 4

Abbreviations and Acronyms

When the following abbreviations are used herein, they have the following meanings:

Example 5

General synthesis reaction scheme

Methods for preparing the compounds of the present invention are illustrated in the Schemes and Examples below. The invention further provides processes for the preparation of compounds of structural formula (I) and formula (II) as defined above. In some cases, the order in which the above schemes are performed can be varied to facilitate the reaction or avoid unwanted reaction products. The following exemplary compounds are provided for illustrative purposes only and should not be construed as limitations on the disclosed invention.

Scheme 1

Compounds of formula (I) can be prepared starting from the heteroaromatic dichlorocarboxylic acid ester A-1 using various substituted phenols in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , NaOH, KOH or other organic bases. It can be synthesized in a seven-step linear synthesis by nucleophilic substitution of Cl adjacent to the carboxylic acid to give the intermediate of type A-2. The intermediate of type A-2 can be further treated with nitromethane in DMSO using an organic base to produce A-3. A-3 can be converted to the corresponding iodo compound by treatment with HI (50%), HI (57%) or HI (40%) to give the intermediate of type A-4. Variously substituted R ₁ groups can be introduced by Pd-mediated or Cu-mediated coupling with intermediates of type A-4 to generate intermediates of type A-5. Carboxylic acids of intermediate type A-6 can be prepared by hydrolyzing the ester intermediate of type A-5 using a base such as aqueous NaOH, KOH or LiOH. Alternatively, intermediate of type A-6 can be prepared by treating intermediate A-5 with aqueous 1-6N HCl. The carboxylic acid (A-6) can be converted to the corresponding acid chloride, which can then be reacted with 3-(substitutedthio)aniline to give A-7. Alternatively, A-7 can be coupled to the carboxylic acid (A-6) and 3-(substituted thio) using standard amide coupling reagents, but not limited to HATU, TBTU, EDC or T3P, in organic solvents and bases such as DIEA. It can be manufactured from aniline. Compounds of formula (I) can be prepared by reacting the intermediate of type A-7 with ammonium carbonate and (diacetoxyiodo)benzene in an organic solvent such as methanol.

Scheme 2

Intermediates of type B-3 can be prepared analogously to the steps described for A-4 in Scheme 1. The intermediate of type B-3 was reacted with methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, TBAI, CuI by using DMF or HMPA as solvent and heating at 25°C-120°C for 1-12 hours. B-4 was obtained by further reacting with. The acid intermediate (B-5) can be prepared from B-4 by a hydrolysis procedure similar to that described in Scheme 1. Intermediates of type B-6 can be prepared from the corresponding acids using standard coupling conditions described in Scheme 1. Compounds of formula (II) can be prepared by treating B-6 with oxone in an organic solvent or mCPBA in DCM. Alternatively, compounds of formula (II) can be prepared from carboxylic acid (B-5) and an appropriately 3-substituted aniline using standard coupling conditions as described in Scheme 1. Compounds of formula (II) can also be prepared by reacting the intermediate of type B-6 with ammonium carbonate and (diacetoxyiodo)benzene in an organic solvent such as methanol.

Scheme 3

Compounds of formula (III) can be prepared by treating B-5 with a substituted aniline or heteroaryl aniline using standard amide coupling reagents, but not limited to HATU, TBTU, EDC or T3P, in organic solvents and bases such as DIEA. You can.

Example 6

Specific synthesis:

Scheme 4, Intermediates 1-5

3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid

Reagents & Conditions: a) 4-fluoro-2-methylphenol, K ₂ CO ₃ , CH ₃ CN, 80°C, 3 hours; b) Nitromethane, Et ₃ N, DMSO, room temperature, 48 hours; c) HI (57%), 55°C, 16 hours; d) Methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, TBAI, CuI, DMF, 90° C., 2 hours; e) LiOH, THF:H ₂ O (5:1), room temperature.

intermediate 1

Step 1: Methyl 6-chloro-3-(4-fluoro-2-methylphenoxy)pyridazine-4-carboxylate: 4-fluoro-2-methylphenol (3.01) in CH ₃ CN (47 mL) g, 23.8 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (4.70 g, 22.7 mmol) and K ₂ CO ₃ (4.71 g, 34.1 mmol) was stirred at 80°C for 3 hours. . The reaction was cooled to room temperature, filtered, and washed with CH3-CN (20 mL). The filtrate was concentrated under vacuum to give a crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 15% EtOAc in heptane gave the title compound methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate. (95.0%) (4.10 g, 58%) was obtained as a light yellow oil. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (s, 1H), 7.29 - 7.20 (m, 2H), 7.16 - 7.06 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H) ). LC-MS: m/z: 297/299 [M+H] ⁺ , (ESI+), RT = 4.26 LCMS method 5.

intermediate 2

Step 2: Methyl 6-chloro-3-(4-fluoro-2-methylphenoxy)-5-methylpyridazine-4-carboxylate: Methyl 6-chloro-3-(4) in DMSO (3.6 mL) To a mixture of -fluoro-2-methylphenoxy)pyridazine-4-carboxylate (1.20 g, 4.04 mmol), nitromethane (1.1 mL, 20.2 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then, triethylamine (0.85 mL, 6.07 mmol) was added to the reaction and stirred at room temperature for 48 hours. The reaction was diluted with water (100 mL) and brine (25 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give the crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane gave the title compound (1.110 g, 85%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.26 - 7.19 (m, 2H), 7.15 - 7.08 (m, 1H), 3.99 (s, 3H), 2.38 (s, 3H), 2.08 (s, 3H) ). LC-MS: m/z 310.95, 312.9 [M+H] ⁺ , (ESI+), RT = 1.27 LCMS method 5.

intermediate 3

Step 3: Methyl 3-(4-fluoro-2-methylphenoxy)-6-iodo-5-methylpyridazine-4-carboxylate: 55% aqueous hydrogen iodide (55%, 24 mL, 0.177 A mixture of methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylate (1.10 g, 3.54 mmol) in mol) was reacted at 40° C. for 16 minutes. Stirred for an hour. The reaction was diluted with water (50 mL) and saturated sodium thiosulfate (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give the title compound methyl 3-(4-fluoro-2-methylphenoxy)-6-iodo-5-methylpyridazine-4-carboxylate ( 42.0%) (1153 mg, 34%) was obtained as a brown oil. LC-MS: m/z 403.0 [M+H]+, (ESI+), RT = 1.29 LCMS method 1.

intermediate 4

Step 4: Methyl 3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: Methyl 3-( in DMF (6.4023 mL) 4-Fluoro-2-methyl-phenoxy)-6-iodo-5-methylpyridazine-4-carboxylate (42%, 1.153 g, 1.20 mmol), iodoguri (0.35 g, 1.81 mmol) , and tetrabutylammonium iodide (0.18 g, 0.482 mmol), methyl difluoro(fluorosulfonyl)acetate (1.16 g, 6.02 mmol) was added, and stirred at 70°C for 2 hours. The reaction was cooled to room temperature, filtered, and washed with EtOAc (2 x 20 mL). The filtrate was washed with brine (50 mL), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 20% EtOAc in heptane gave the title compound (97.0%) (425 mg, 99%) as a light yellow oil. LC-MS: m/z 345.0 [M+H]+, (ESI+), RT = 1.33 LCMS Method 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.31 - 7.23 (m, 2H), 7.14 ( td, J = 8.6, 3.2 Hz, 1H), 4.02 (s, 3H), 2.48 - 2.44 (m, 3H), 2.09 (s, 3H).

intermediate 5

Step 5: 3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid: THF (4.5806 mL): Water (0.9161 mL) A mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (97%, 425 mg, 1.20 mmol) To this, lithium hydroxide (149 mg, 5.99 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The aqueous layer was extracted with EtOAc (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound (407 mg, 99%) as a light yellow solid.

Intermediates 6-15 listed in Table 1 were prepared by procedures similar to those described for Step 1 of Scheme 4 using the appropriate starting materials.

Table 1.

Intermediates 16-24 listed in Table 2 were prepared by procedures similar to those described for Step 2 of Scheme 4 using the appropriate starting materials.

Table 2.

Intermediates 25-35 listed in Table 3 were prepared by procedures similar to those described for Step 3 of Scheme 4 using the appropriate starting materials.

Table 3.

Intermediates 36-46 listed in Table 4 were prepared by procedures similar to those described for Step 4 of Scheme 4 using the appropriate starting materials.

Table 4.

Intermediates 47-56 listed in Table 5 were prepared by procedures similar to those described for Step 5 of Scheme 4 using the appropriate starting materials.

Table 5.

Intermediate 57

4-(Cyclobutoxy)-2,3-difluoro-phenol

Reagents & Conditions: a) Tosyl chloride, TEA, DCM, room temperature, 18 hb) 4-bromo-2,3-difluorophenol, K ₂ CO ₃ , DMF, 90°C, 4 hc) KOH, (1{ E},4{E})-1,5-diphenylpenta-1,4-dien-3-one;palladium, di-tert-butyl[3,4,5,6-tetramethyl-2',4 ',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane, 1:1 1,4-dioxane/water, 100°C, 18 h

Step 1: Cyclobutyl 4-methylbenzenesulfonate: 4-methylbenzenesulfonyl chloride (635 mg, 3.33 mmol) in a solution of cyclobutanol (0.22 mL, 2.77 mmol) in DCM (6 mL) under an atmosphere of nitrogen. Triethylamine (0.46 mL, 3.33 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (5 mL) and extracted with DCM (2x5 mL). The organic phase was dried (MgSO ₄ ), filtered and concentrated to give a clear oil. Cyclobutyl 4-methylbenzenesulfonate (97%) (362 mg, 1.599 mmol, 58%) purified by FCC (Biotage Isolera, SiO ₂ gradient elution, 0 to 20% EtOAc in heptane) was obtained as a clear oil. m/z: 227.1 [M+H] ⁺ , (ESI+), RT = 0.91 METCR1704 (2 min uPLC gradient method for IPC).

Step 2: 1-Bromo-4-(cyclobutoxy)-2,3-difluoro-benzene: 4-bromo-2,3-difluorophenol (1.40 g, 6.70) in DMF (10 mL) mmol) and cyclobutyl 4-methylbenzenesulfonate (1.82 g, 8.04 mmol) was added dipotassium carbonate (1.39 g, 10.0 mmol). The mixture was heated at 90° C. for 4 hours. The mixture was allowed to cool to room temperature, then diluted with ethyl acetate (60 mL) and washed with water (3x 30 mL) and brine (30 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give an orange oil. Purified by FCC (Biotage Isolera, SiO ₂ gradient elution, 0 to 10% EtOAc in heptane) to give 1-bromo-4-(cyclobutoxy)-2,3-difluoro-benzene (76% ) (0.983 g, 3.737 mmol, 43%) was obtained as a clear oil. LC-MS: m/z 263.2 [M] ⁺ , (ESI+), RT = 1.10 METCR1704 (2 min uPLC gradient method for IPC).

Step 3: 4-(Cyclobutoxy)-2,3-difluoro-phenol: 1-bromo-4-(cyclobutoxy) in 1,4-dioxane (5 mL) and water (5 mL) A mixture of -2,3-difluoro-benzene (980 mg, 3.73 mmol) and potassium hydroxide (418 mg, 7.45 mmol) was degassed by nitrogen bubbling for 10 minutes and then di-tert-butyl[3, 4,5,6-tetramethyl-2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane (143 mg, 0.298 mmol) and (1{E},4 {E})-1,5-diphenylpenta-1,4-dien-3-one;palladium (68 mg, 0.0745 mmol) was added, and the reaction was stirred at 10°C for 18 hours. The pH was adjusted to ~3 using 1M HCl and the mixture was extracted with ethyl acetate (3 x 8 mL). The combined organics were dried (MgSO4), filtered and concentrated to give a brown oil. Purified by FCC in heptane (Biotage Isolera, SiO2 gradient elution, 0 to 5% EtOAc) to give 4-(cyclobutoxy)-2,3-difluoro-phenol (90%) (622 mg, 3.107 mmol, 75%) was obtained as a light orange solid. LC-MS: m/z 199.1 [MH] ^- , (ESI-), RT = 0.82 METCR1704 (2 min uPLC gradient method for IPC).

Intermediate 58 and Intermediate 59

tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate [Intermediate 58] and tert-butyl (R)-((3-aminophenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate [Intermediate 59].

Reagents & Conditions: NH ₄ (OAc), PhI(OAc) ₂ , EtOH, room temperature, 16 hours; b) t-BuOK, (Boc) ₂ O, t-BuOH, reflux, 10 hours; c) Pd(OH) ₂ , H ₂ , MeOH, room temperature, 2 hours; d) SFC purification

Step 1: Imino(methyl)(3-nitrophenyl)-λ ⁶ -sulfanone: Methyl(3-nitrophenyl)sulfan (8.2 g, 48.5 mmol) and ammonium acetate (5.6 g, 72.7 mmol) in EtOH (120 mL) mmol), PhI(OAc) ₂ (31.2 g, 97 mmol) was added in 1 part. The reaction mixture was stirred at room temperature under atmosphere for 16 hours. The mixture was concentrated directly to give a residue, which was purified by silica gel chromatography column (PE:EA=5:1 to 1:3) to give imino(methyl)(3-nitrophenyl)-λ ⁶ -sulphenyl. Fanone was obtained as a white solid (7.0 g, 72%). MS (ESI+): m/z actual value 201.03 [M+H] ⁺ .

Step 2: tert-Butyl (methyl(3-nitrophenyl)(oxo)-λ ⁶ -amino-sulfanylidene)carbamate: Imino(methyl)(3) in t-BuOH (200 mL) cooled with ice water bath. To a solution of -nitrophenyl)-λ ⁶ -sulfanone (3.5 g, 17.5 mmol) was added t-BuOK (3.9 g, 35.0 mmol) under N ₂ protection. Subsequently, (Boc) ₂ O (7.6 g, 35.0 mmol) was added slowly and the reaction mixture was refluxed for 10 hours. The reaction mixture was quenched with saturated NH ₄ Cl solution (200 mL) and extracted with EA (200 mL x 2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give a residue, which was purified by silica gel chromatography column (PE:EA=5:1 to 1:1) to give tert- Butyl (methyl(3-nitrophenyl)(oxo)-λ ⁶ -sulfanylidene)carbamate was obtained as a yellow solid (1.8 g, 34%). LC-MS(ESI+): m/z 301.09 [M+H] ⁺ .

Step 3: (3-aminophenyl)(imino)(methyl)-λ ⁶ -sulfanone: tert-butyl (methyl(3-nitrophenyl)(oxo)-λ ⁶ -sulfanylidene in MeOH (30 mL) ) Pd(OH) ₂ (300 mg) was added to a solution of carbamate (1.8 g, 6 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite and washed with MeOH (100 mL). The filtrate was concentrated to give a residue, which was redissolved in EA (30 mL) and the resulting solution was filtered again through Celite and washed with EA (100 mL). The filtrate was concentrated to give tert-butyl ((3-aminophenyl) (methyl) (oxo)-λ ⁶ -sulfanylidene) carbamate (1.4 g, 86%) as an off-white solid. MS (ESI+): m/z actual value 271.10 [M+H] ⁺ .

Step 4: SFC separation: Chiral separation of racemic product by chiral HPLC Conditions: Column: Daicel Chiralpak IG, 250 mm x 20 mm ID, 5 μm; Mobile phase A: CO ₂ / MeOH [0.2% NH ₃ (7M solution in MeOH)] = 70/30; Flow rate: 60 g/min; 214 nm. Temperature: 35°C was used for separation. The first eluting isomer tert-butyl (S)-((3-aminophenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate [Intermediate 58]. ^1H NMR (DMSO-d ₆ ) δ7.26 (t, 1H), 7.08(s, 1H), 6.97(d, 1H), 6.83(d, 1H), 5.71(s, 2H), 3.28(s, 3H), 1.27 (s. 9H) and the second eluting isomer tert-butyl (R)-((3-aminophenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate [Intermediate 59]. ^1H NMR (DMSO-d ₆ ) δ7.26 (t, 1H), 7.08(s, 1H), 6.97(d, 1H), 6.83(d, 1H), 5.71(s, 2H), 3.28(s, 3H), 1.27(s. 9H).

Example 7

Compound 1: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carbox amides

Reagents & Conditions: a) 3-(Methylsulfonyl)aniline, 50% solution of propylphosphonic anhydride in EtOAc, N,N-diisopropylethylamine (DIEA), DCM, room temperature.

N,N-Diisopropylethylamine (DIEA) (0.16 mL, 0.908 mmol), 3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine- A mixture of 4-carboxylic acid (0.100 g, 0.303 mmol) and 3-(methylsulfonyl)aniline (0.062 g, 0.363 mmol) was dissolved in DCM (4.8 mL) at room temperature under nitrogen. To the mixture was added a 50% solution of propylphosphonic anhydride in EtOAc (50%, 0.36 mL, 0.606 mmol) in 1 portion. The reaction mixture was stirred at room temperature for 4 hours. The reaction was then stirred at 55°C for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum to give a crude residue. Purification by preparative LC method P1 gave the title compound (0.025 g, 17%) as a white solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 8.38 (t, J = 1.8 Hz, 1H), 7.90 (ddd, J = 7.9, 2.0, 1.2 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 8.9, 5.0 Hz, 1H), 7.24 (dd, J = 9.4, 3.1 Hz, 1H), 7.14 (td) , J = 8.5, 3.1 Hz, 1H), 3.24 (s, 3H), 2.54 - 2.51 (m, 3H), 2.12 (s, 3H). LC-MS: m/z 484.0 [M+H] ⁺ , (ESI+), RT = 4.24 LCMS method 5.

Example 8

Compound 2: 5-methyl-N-(3-methylsulfonylphenyl)-3-[2-methyl-4-(trifluoromethyl)phenoxy]-6-(trifluoromethyl)pyridazine-4- Carboxamide

The title compound was reacted with 5-methyl-3-(2-methyl-4-(trifluoromethyl)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 3-(methylsulfonyl) It was prepared by a method similar to that described for compound 1 using aniline. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (s, 1H), 8.37 (t, J = 1.8 Hz, 1H), 7.93 - 7.87 (m, 1H), 7.80 - 7.66 (m, 4H), 7.51 (d, J = 8.4 Hz, 1H), 3.24 (s, 3H), 2.56 - 2.53 (m, 3H), 2.21 (s, 3H). m/z: 534.1 [M+H] ⁺ , (ESI+), RT = 3.81 LCMS Method 4

Example 9

Compound 3: 5-methyl-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine- 4-carboxamide

3 using 5-methyl-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (85 mg, 0.202 mmol) A mixture of -(methylsulfonyl)aniline (41 mg, 0.242 mmol) was dissolved in DMF (0.5085 mL) under nitrogen at room temperature. Next, N-ethyl-N-isopropyl-propan-2-amine (0.070 mL, 0.403 mmol) was added, followed by N-[(dimethylamino)(3H-[1,2,3]triazolo[4 ,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (77 mg, 0.202 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with brine (10 mL) and extracted with EtOAc (2 x 10 mL). The organic part was washed with 1M HCl (10 mL), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the crude residue, which was purified using purification method Prep1 to give 5-methyl-3-(2- Methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (51 mg, 46%) was obtained as an off-white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.41 (t, J = 1.9 Hz, 1H), 7.97 (ddd, J = 8.1, 2.1, 1.1 Hz, 1H), 7.79 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.29 - 7.25 (m, 1H), 7.21 (dd, J = 8.8, 2.7 Hz, 1H), 3.15 (s, 3H), 2.62 - 2.57 (m, 3H), 2.21 (s, 3H). m/z: 550.5 [M+H] ⁺ , (ESI+), RT = 4.50 LCMS Method 5.

Example 10

Compound 4: 3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-car Voxamide

Reagents & Conditions: a) 3-Methanesulfonylaniline, HATU, DIEA, DMF, rt

3-(4-Cyano-2-methoxyphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.060, 0.170 mmol), 3- in DMF (3 mL) To a mixture of methanesulfonylaniline (0.029 g, 0.170 mmol), HATU (0.097 g, 0.255 mmol) was added DIEA (0.089 mL, 0.510 mmol) at 25°C and stirring was continued for an additional 16 hours at 25°C. . The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2x 30 mL). The combined EtOAc layers were washed with 1M LiCl (10 mL) followed by brine (20 mL). The EtOAc layer was dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The crude product was chromatographed on SiO ₂ with a gradient of 0 to 10% EtOAc in DCM to give 3-(4-cyano-2-methoxyphenoxy)-N-(3-methanesulfonylphenyl)-5-methyl- 6-(Trifluoromethyl)pyridazine-4-carboxamide (0.028 g, 33%) was obtained. ^1H NMR (300 MHz, CDCl ₃ ) δ 8.52 (s, 1H), 8.15 - 7.97 (m, 2H), 7.77 (dt, J = 7.9, 1.3 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 1.5 Hz, 2H), 7.30 (s, 1H), 3.89 (s, 3H), 3.09 (s, 3H), 2.67 (q, J = 1.5 Hz, 3H). LC-MS: m/z 505.3 [MH] ⁺

Compounds 5-7 listed in Table 6 were prepared by procedures similar to those described for compound 4.

Table 6.

Example 11

Compound 8: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

Reagents & Conditions: DIEA, solution of propylphosphonic anhydride in EtOAc (50%; v/v), DMAP, 3-(methylsulfanyl)aniline, DCM, 55°C, 16 hours.

3-(4-fluoro-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (100 mg, 0.303 mmol) in DCM (1.9151 mL) at room temperature. To a mixture of N-ethyl-N-isopropyl-propan-2-amine (0.12 mL, 0.666 mmol) and N,N-dimethylpyridin-4-amine (7.4 mg, 0.0606 mmol) followed by 50% propyl in EtOAc. Phosphonic anhydride solution (50%, 0.36 mL, 0.606 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 3-(Methylsulfanyl)aniline (51 mg, 0.363 mmol) was added to the reaction. The reaction mixture was stirred at room temperature for 10 minutes and then at 55°C for 16 hours. Volatiles were removed under vacuum. 3-(4-fluoro-2-methylphenoxy)-5-methyl-N- was purified by chromatography on silica, eluting with a gradient from 0 to 100% EtOAc in heptane, followed by 0-60% MeOH in EtOAc. (3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (43.0%) (110 mg, 35%) was obtained as a yellow solid. LC-MS: m/z 452.6 [M+H] ⁺ , (ESI+), RT = 4.81 LCMS method 5.

Compounds 9-13 listed in Table 7 were prepared by similar procedures described for compound 8.

Table 7.

Example 12

Compound 14: 3-(4-cyano-2-methylphenoxy)-5-methyl-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxyx amides

Reagents & Conditions: HATU, 3-(methylsulfanyl)aniline, DIEA, DMF, room temperature, 16 hours.

3-(4-Cyano-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.300 g, 0.890 mmol), 3 in DMF (10 mL) To a mixture of -(methylsulfanyl)aniline (0.124 g, 0.890 mmol) and HATU (0.676 g, 1.78 mmol) was added DIEA (0.0345 g, 2.67 mmol) at room temperature. The resulting mixture was stirred for a further 16 hours, at the end of this period water (10 mL) was added and extracted with EtOAc (2x40 mL). The combined EtOAc layers were washed with 1M LiCl (20 mL) followed by brine (30 mL). The EtOAc layer was dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The crude material was chromatographed on SiO2 with a gradient of 0-50% EtOAc in hexanes to give 3-(4-cyano-2-methylphenoxy)-5-methyl-N-[3-(methylsulfanyl)phenyl]- 6-(Trifluoromethyl)pyridazine-4-carboxamide (0.165 g, 40.46%) was obtained. ^1H NMR (300 MHz, CDCl3) δ 7.72 - 7.49 (m, 3H), 7.37 - 7.21 (m, 4H), 7.19 - 7.06 (m, 1H), 2.63 (q, J = 1.5 Hz, 3H), 2.52 (s, 3H), 2.23 (s, 3H). LC-MS: m/z 457.3[MH] ⁺ .

Compounds 15-19 listed in Table 8 were prepared by procedures similar to those described for compound 14.

Table 8.

Example 13

Compound 20: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide

Reagents & Conditions: a) Ammonium carbonate, (diacetoxyiodo)benzene, MeOH, room temperature, 24 hours.

3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (43% ) (0.090 g, 0.0857 mmol) was dissolved in methanol (0.3518 mL) and treated with ammonium carbonate (0.012 g, 0.13 mmol) and (diacetoxyiodo)benzene (0.064 mg, 0.197 mmol), respectively. was added in 1 part. The resulting mixture was stirred at room temperature for 24 hours. The solvent was removed under vacuum. Purification by chromatography gave the title compound (0.032 g, 75%) as a light brown solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.35 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.76 - 7.71 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 8.9, 5.0 Hz, 1H), 7.24 (dd, J = 9.3, 3.0 Hz, 1H), 7.14 (td, J = 8.5, 3.1 Hz) , 1H), 4.25 (s, 1H), 3.07 (s, 3H), 2.52 (s, 3H), 2.12 (s, 3H). LC-MS: m/z 482.9 [M+H] ⁺ , (ESI+), RT = 3.83 LCMS method 5.

Compounds 21-29 listed in Table 9 were prepared by similar procedures described for compound 20.

Table 9.

Example 14

Compounds 30 and 31: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine -4-Carboxamide chiral separation

3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxyx Chiral purification of the amide (compound 20) was performed using preparative chiral HPLC on Chiralpak AD-H, (20 x 250 m) 5 μm, eluting with a mixture of heptane: ethanol (70:30), flow rate 18 mL/min. did. Fractions containing the product were evaporated and isolated as a sticky oil, which was redissolved in 1:1 MeCN:water (1 mL) and lyophilized to give the first eluting isomer (compound 30) (39 mg, 32%) as an off-white color. As a solid. LC-MS: m/z: 483.2 [M+H] ⁺ , (ESI+), RT = 3.15 LCMS Method 6. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 8.38 - 8.33 (m, 1H), 7.90 - 7.83 (m, 1H), 7.77 - 7.70 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.29 (dd, J = 8.8, 5.0 Hz, 1H), 7.24 (dd, J = 9.4, 3.0 Hz, 1H), 7.14 (td, J = 8.7, 3.2 Hz, 1H), 4.25 (s, 1H), 3.07 (s, 3H), 2.52 - 2.52 (m, 3H) , 2.12 (s, 3H). Analytical method: Mobile phase 70:30 heptane:ethanol, column Chiralpak AD-H, 4.6 x 250 mm, 5 μm flow rate 1 mL/min. and the second eluting isomer (Compound 31) (0.038 mg, 32%) as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (t, J = 1.9 Hz, 1H), 7.96 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.84 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.8, 4.9 Hz, 1H), 7.09 (dd, J = 9.1, 3.1 Hz, 1H), 7.01 (td, J = 8.5, 3.1 Hz, 1H), 3.17 (s, 3H), 2.62 - 2.55 (m, 3H), 2.17 (s, 3H). m/z: 483.5 [M+H] ⁺ , (ESI+), RT = 3.82 LCMS method 5 was obtained.

Example 15

Compounds 32 and 33: 5-methyl-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoro Methyl)pyridazine-4-carboxamide chiral separation

5-methyl-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine- 4-Carboxamide was prepared by a similar procedure described for compound 20, using preparative chiral HPLC on Chiralpak AD-H, (20 x 250 m) 5 μm as a mixture of heptane: ethanol (70:30); It was purified by eluting at a flow rate of 18 mL/min. Fractions containing the product were isolated as a sticky oil by evaporation, redissolved in 1:1 MeCN:water (1 mL), and lyophilized to give the first eluting isomer (compound 32) (63 mg, 37%) as beige. Obtained as a colored solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.90 - 7.83 (m, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.44 - 7.38 (m, 2H), 7.35 - 7.30 (m, 1H), 4.25 (s, 1H), 3.07 (d, J = 0.8 Hz, 3H) ), 2.54 - 2.52 (m, 3H), 2.16 (s, 3H). m/z: 549.2 [M+H]+, (ESI+), RT=3.60 LCMS method 6 and the second eluting isomer (compound 33) (54 mg, 31%) was obtained as a beige solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 8.35 (t, J = 1.9 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.35 - 7.29 (m, 1H), 4.25 (s, 1H), 3.10 - 3.01 (m, 3H), 2.53 - 2.52 (m, 3H), 2.16 (s, 3H). m/z: 549.2 [M+H] ⁺ , (ESI+), RT = 3.60 LCMS Method 6.

Example 16

Compounds 34 and 35: 5-methyl-3-(2-methyl-4-(trifluoromethyl)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoro Methyl)pyridazine-4-carboxamide chiral separation

5-methyl-3-(2-methyl-4-(trifluoromethyl)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine- 4-Carboxamide was prepared by a similar procedure described for compound 20 and purified using preparative chiral HPLC on Chiralpak AD-H, (20 x 250 m) 10 μm. Purified by HPLC at 5 μm, eluting with a mixture of heptane:ethanol (85:15), flow rate 18 mL/min. Fractions containing the product were evaporated to yield the first eluting isomer (compound 34) (99 mg, 29%). ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.91 - 7.84 (m, 1H), 7.81 - 7.77 (m, 1H), 7.76 - 7.68 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.25 (s, 1H), 3.10 - 3.04 (m, 3H), 2.55 - 2.53 (m, 3H), 2.21 (s, 3H). LC-MS: m/z 533.6 [M+H] ⁺ , (ESI+), RT = 4.15 LCMS method 5 and the second eluting isomer (Compound 35) (92 mg, 27%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.81 - 7.77 (m, 1H), 7.76 - 7.67 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 4.25 (s, 1H), 3.11 - 3.05 (m, 3H), 2.55 - 2.52 (m, 3H), 2.21 (s, 3H). LC-MS: m/z: 533.6 [M+H] ⁺ , (ESI+), RT = 4.14 LCMS method 5 was obtained.

Example 17

Compounds 1401-1429 listed in Table 10 were prepared by procedures similar to those described for compound 14.

Table 10.

Example 18

Compound 1430: 6-(3-Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-pyridazin-4-yl-pyridazine- 4-carboxamide

Reagents & Conditions: a) (4R)-4-Hydroxy-L-proline, 3-fluoroazetidine hydrochloride, tripotassium phosphate, copper iodide, CH ₃ CN, DMSO, 50°C, 104 hours; b) LiOH, THF:H ₂ O (7:1, v/v), room temperature, 2 hours; c) HATU, pyridazine-4-amine, DIPEA, DMF, room temperature, 2 hours.

Step 1: Methyl 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylate: (4R )-4-Hydroxy-L-proline (16 mg, 0.124 mmol) was dissolved in methyl 3-(4-fluoro-2-methyl-phenoxy)- in anhydrous acetonitrile (2.5 mL) and anhydrous DMSO (2 mL). 6-Iodo-5-methyl-pyridazine-4-carboxylate (250 mg, 0.622 mmol), 3-fluoroazetidine hydrochloride (139 mg, 1.24 mmol), copper iodide (12 mg, 0.0622 mmol) and tripotassium phosphate (396 mg, 1.86 mmol) were added to the N ₂ degassed mixture and the reaction was stirred at 50° C. for 80 hours. Additional reagents (4R)-4-hydroxy-L-proline (16 mg, 0.124 mmol), methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-pyri Dajin-4-carboxylate (250 mg, 0.622 mmol), 3-fluoroazetidine hydrochloride (1:1) (139 mg, 1.24 mmol), copper iodide (1+) (12 mg, 0.0622 mmol) ) and tripotassium phosphate (396 mg, 1.86 mmol) were added and the reaction was stirred at 70°C for an additional 24 hours. The reaction was diluted with EtOAc (~60 mL), washed sequentially with 1M aqueous HCl, water and brine, dried over sodium sulfate, and concentrated to dryness in vacuo to give the crude title compound methyl 6-(3-fluoroazetidine-1). -1)-3-(4-Fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylate (699 mg, 100%) as a brown gum in estimated 100% molar yield. was obtained, and it was used as is in the subsequent step without further analysis or purification. m/z: 350 [M+H] ⁺ , (ESI+), RT = 0.89 min METCR1704 (2 min uPLC gradient method for IPC).

Step 2: 6-(3-Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-pyridazine-4-carboxylic acid: Lithium hydroxide ( 93 mg, 3.73 mmol) was dissolved in methyl 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy) in THF (4.2 mL) and water (0.6 mL). -5-Methyl-pyridazine-4-carboxylate (217 mg, 0.622 mmol) was added to the mixture and the mixture was stirred at room temperature for 16 hours. The reaction was stirred for an additional 24 hours and then heated at 40° C. for an additional 8 hours (total of 56 hours). The reaction was diluted with water (20 mL) and the pH was adjusted to ~1-2 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3 x 20 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the title compound 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl- Phenoxy)-5-methyl-pyridazine-4-carboxylic acid (59.0%) (353 mg, 100%) was obtained as a brown solid, which was used in the next step without further analysis or purification. LC-MS: m/z 336 [M+H] ⁺ , (ESI+), RT = 0.46 min METCR1704 (2 min uPLC gradient method for IPC).

Step 3: 6-(3-Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-pyridazin-4-yl-pyridazine- 4-Carboxamide: HATU (130 mg, 0.342 mmol) was dissolved in 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy) in DMF (2 mL). )-5-methyl-pyridazine-4-carboxylic acid (104 mg, 0.311 mmol) and N-ethyl-N-isopropyl-propan-2-amine (119 uL, 0.684 mmol) at room temperature and , the reaction was stirred at room temperature for 5 minutes, then pyridazin-4-amine (44 mg, 0.466 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Purification by high pH preparative HPLC (initial method) gave the title compound 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl- N-Pyridazin-4-yl-pyridazine-4-carboxamide (20 mg, 0.0478 mmol, 15%) was obtained as an off-white solid. ^1H NMR (400 MHz, MeOH-d ₄ ) δ 9.31 (d, J = 1.9 Hz, 1H), 9.08 (d, J = 5.9 Hz, 1H), 8.19 (dd, J = 5.9, 2.7 Hz, 1H) , 7.11 (dd, J = 8.9, 4.9 Hz, 1H), 7.00 (dd, J = 9.2, 3.0 Hz, 1H), 6.97 - 6.88 (m, 1H), 5.43 (dm, J = 57.8, 9.4, 5.9, 3.5 Hz, 1H), 4.55 - 4.41 (m, 2H), 4.31 - 4.18 (m, 2H), 2.30 (s, 3H), 2.15 (s, 3H). m/z: 413.3 [M+H] ⁺ , (ESI+), RT = 2.45 LCMS Method 6

Example 19

Compound 1431: 6-(3-Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl ]Pyridazine-4-carboxamide

Reagents & Conditions: a) HATU, 3-(methylsulfanyl)aniline, DIPEA, DMF, room temperature, 2 hours. b) PIDA, (NH4) ₂ CO ₃ , MeOH, room temperature, 3 days.

Step 1: 6-(3-Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine -4-Carboxamide: HATU (130 mg, 0.342 mmol) was dissolved in 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenocyl) in DMF (2 mL). Si)-5-methyl-pyridazine-4-carboxylic acid (104 mg, 0.311 mmol) and N-ethyl-N-isopropyl-propan-2-amine (119 uL, 0.684 mmol) were added at room temperature. The reaction was stirred at room temperature for 5 minutes, then 3-(methylsulfanyl)aniline (57 uL, 0.466 mmol) was added, and the reaction was stirred at room temperature for 2 hours.

The reaction mixture was diluted with EtOAc (~50 mL) and washed with water (3 x ~50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Purification by FCC (Biotage Isolera, SiO2, gradient elution 10-50% EtOAc:heptane) gave the title compound 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2 -Methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (90.0%) (30 mg, 0.0591 mmol, 19%) was obtained as a yellow gum. LC-MS: m/z: 457 [M+H] ⁺ , (ESI+), RT = 0.95 min METCR1704 (2 min uPLC gradient method to IPC)

Step 2: 6-(3-Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl ]Pyridazine-4-carboxamide: Phenyl iodonium di-acetate (PIDA) (49 mg, 0.151 mmol) and diammonium carbonate (10 mg, 0.105 mmol) were 6-(3-) in methanol (1 mL). Fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (30 mg, 0.0657 mmol) was added to the solution at room temperature, and the reaction was stirred at room temperature for 3 days. The reaction mixture was concentrated to dryness under vacuum to give the crude product. The residue was purified by low pH preparative HPLC (initial method). Product containing fractions were combined and solvent removed under vacuum to give the title compound 6-(3-fluoroazetidin-1-yl)-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N. -[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (100.0%)) (12 mg, 0.0246 mmol, 37%) was obtained as an off-white solid. ^1H NMR (400 MHz, CD3OD) δ 8.43 (t, J = 1.9 Hz, 1H), 7.99 - 7.90 (m, 1H), 7.86 - 7.76 (m, 1H), 7.64 (t, J = 8.0 Hz, 1H) ), 7.11 (dd, J = 8.9, 4.9 Hz, 1H), 7.01 (dd, J = 9.1, 3.0 Hz, 1H), 6.99-6.93 (m, 1H), 5.52 - 5.34 (dm, J = 57.8, Hz) , 1H), 4.48 m, 2H), 4.24 - 4.19 (m, 2H), 3.17 (s, 3H), 2.30 (s, 3H), 2.16 (s, 3H). m/z: 488.3 [M+H] ⁺ , (ESI ⁺ ), RT = 2.65 min LCMS method 6.

Example 20

Compound 1432: 6-Cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

Reagents & Conditions: a) LiOH, THF, water, room temperature, 40 hours. b) 3-(methylsulfanyl)aniline, HATU, DIPEA, DMF, room temperature, 40 hours. b) HATU, 3-(methylsulfanyl)aniline, DIPEA, DMF, room temperature, 16 hours. c) Pd(OAc) ₂ , DPEphos, K ₄ [Fe(CN) ₆ ]·3H ₂ O, Na ₂ CO ₃ , 1,4-dioxane, water, NMP 70°C, 21 h. d) PIDA, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 16 h.

Step 1: 3-(2-Fluoro-4-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid: Lithium hydroxide (126 mg, 5.05 mmol) was dissolved in THF (11). mL) and methyl 3-(2-fluoro-4-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (677 mg, 1.68 mmol) in water (1.7 mL). was added to the mixture, and the mixture was stirred at room temperature for 40 hours. The reaction was diluted with water (20 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3 x 20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the title compound 3-(2-fluoro-4-methyl-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxyl. The acid (617 mg, 1.59 mmol, 94%) was obtained as a light yellow solid, which was used as such in the next step. LC-MS: m/z: 389 [M+H] ⁺ , (ESI+), RT = 0.61 METCR1410 typical 2 min.

Step 2: 3-[2,6-difluoro-4-(trifluoromethoxy)phenoxy]-5-methyl-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyri Minced-4-carboxamide: HATU (665 mg, 1.75 mmol) was dissolved in 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-pyridazine in DMF (11.5 mL). -4-Carboxylic acid (617 mg, 1.59 mmol) and N-ethyl-N-isopropyl-propan-2-amine (555 uL, 3.18 mmol) were added at room temperature and the reaction was incubated at room temperature for 5 minutes. After stirring, 3-(methylsulfanyl)aniline (235 uL, 1.91 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 50 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Purification by FCC (Biotage Isolera, SiO ₂ gradient elution 10-30% EtOAc:heptane) gave the title compound 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl. -N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (682 mg, 68%) was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (s, 1H), 7.37 - 7.26 (m, 3H), 7.19 - 7.04 (m, 2H), 6.94 (dd, J = 8.8, 3.0 Hz, 1H), 6.86 (td, J = 8.3, 3.1 Hz, 1H), 2.69 - 2.52 (m, 3H), 2.50 (s, 3H), 2.15 (d, J = 4.6 Hz, 3H). m/z: 510 [M+H] ⁺ , (ESI+), RT = 1.02 min METCR1410 typical 2 min

Step 3: 6-Cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: Palladium acetate ( 4.4 mg, 0.0196 mmol) was dissolved in 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N in 1,4-dioxane (0.28 mL) and water (0.28 mL). -(3-methylsulfanylphenyl)pyridazine-4-carboxamide (50 mg, 0.0982 mmol), potassium hexacyanoferate(II) trihydrate (36 mg, 0.0982 mmol), sodium carbonate (21 mg, 0.196) mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (21 mg, 0.0393 mmol) were added to the N ₂ degassed stirred solution. The reaction mixture was heated in a pressure vial at 70° C. for 1 hour. The reaction appeared heterogeneous, so NMP (0.25 mL) was added and the reaction was stirred at 70° C. overnight (20 hours). The reaction mixture was diluted with EtOAc (30 mL), washed with water (3 x 20 mL) and brine, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo to give the crude product (˜130 mg). Purification by FCC (Biotage Isolera, SiO ₂ , gradient elution 0-50% EtOAc:heptane) gave the title compound 6-cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl. -N-(3-Methylsulfanylphenyl)pyridazine-4-carboxamide (99.0%) (30 mg, 0.0727 mmol, 74%) was obtained as a yellow solid. LC-MS: m/z: 409 [M+H] ⁺ , (ESI+), RT = 0.99 min METCR1410 typical 2 min

Step 4: 6-Cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-[3(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide: Phenyl iodo Phenyl di-acetate (PIDA) (54 mg, 0.169 mmol) and diammonium carbonate (10 mg, 0.110 mmol) were reacted with 6-cyano-3-(4-fluoro-2-methyl-phenocyl) in methanol (1 mL). Si)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (30 mg, 0.0734 mmol) was added to a solution at room temperature, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness under vacuum to give the crude product. Purification by FCC (Biotage Isolera, gradient elution 0-100% EtOAc:heptane, Germany) afforded the title compound in less than the required % purity and the product was therefore further subjected to low pH preparative HPLC (initial method). It was purified by . The product containing fractions were combined and the solvent was removed by lyophilization under vacuum overnight to give the title compound 6-cyano-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-( Methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (99.0%) (6.1 mg, 0.0137 mmol, 19%) was obtained as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (t, J = 1.9 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.87 - 7.81 (m, 1H), 7.67 (t, J = 8.0 Hz) , 1H), 7.21 (dd, J = 8.9, 4.9 Hz, 1H), 7.09 (dd, J = 9.0, 3.0 Hz, 1H), 7.06 - 6.97 (m, 1H), 3.17 (s, 3H), 2.62 ( s, 3H), 2.16 (s, 3H). LC-MS: m/z 440 [M+H] ⁺ , (ESI+), RT = 2.83 min MET-uPLC-AB-101 (7 min, low pH).

Example 21

Compound 1433: 6-Cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

Reagents & Conditions: a) Pd(PPh ₃ ) ₄ , CyclopropylSnBu ₃ , Toluene, 70°C, 16h. b) PIDA, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 4 days.

Step 1: 6-Cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: Palladium-tri Phenylphosphane (1:4) (18 mg, 0.0159 mmol) was dissolved in 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N- in anhydrous toluene (0.5 mL). (3-methylsulfanylphenyl)pyridazine-4-carboxamide (81 mg, 0.159 mmol) and tributyl(cyclopropyl)stannane were added to the N ₂ degassed stirred solution and the reaction mixture was incubated for 16 minutes at 70°C. It was stirred in the pressure vial for an hour. The reaction mixture was concentrated to dryness under vacuum to give the crude product. Purification by FCC (Biotage Isolera, SiO ₂ , gradient elution 0-30% EtOAc:heptane) gave the title compound 6-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5- Methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (66.0%) (98 mg, 0.153 mmol, 96%) was obtained as a light yellow oil. LC-MS: m/z 424 [M+H] ⁺ , (ESI+), RT = 1.00 min METCR1410 typical 2 min

Step 2: 6-Cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide: Phenyl Io Donium di-acetate (PIDA) (226 mg, 0.703 mmol) and diammonium carbonate (43 mg, 0.458 mmol) were dissolved in 6-cyclopropyl-3-(4-fluoro-2-methyl-) in methanol (2.2 mL). Phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (66%, 98 mg, 0.153 mmol) was added at room temperature, and the reaction was incubated at room temperature for 4 days. It was stirred for a while. The reaction mixture was concentrated under reduced pressure and purified by column chromatography Biotage Isolera SiO ₂ , gradient elution (0-100% EtOAc:heptane). The product was below the required purity and was therefore purified by low pH preparative HPLC (initial method). Product containing fractions were combined and the solvent was removed by lyophilization under vacuum overnight to yield the title compound 6-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-( Methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (100.0%) (22 mg, 0.0477 mmol, 31%) was obtained as an off-white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.45 (t, J = 1.9 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.87 - 7.78 (m, 1H), 7.65 (t, J = 8.0 Hz) , 1H), 7.13 (dd, J = 8.9, 4.9 Hz, 1H), 7.03 (dd, J = 9.1, 3.0 Hz, 1H), 6.95 (td, J = 8.5, 3.1 Hz, 1H), 3.17 (s, 3H), 2.54 (s, 3H), 2.24 (p, J = 6.6 Hz, 1H), 2.15 (s, 3H), 1.09 (d, J = 6.4 Hz, 4H). LC-MS: m/z 455 [M+H] ⁺ , (ESI+), RT = 2.63 min MET-uPLC-AB-101 (7 min, low pH).

Example 22

Compound 1434: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(prop-1-yne-1- 1) Pyridazine-4-carboxamide

Reagents & Conditions: a) PIDA, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 5 hours. b) prop-1-yne (1 M in THF), PdCl ₂ (dppf), CuI, THF 70°C

Step 1: 3-(4-Fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide: Phenyl iodonium di-acetate (PIDA) (780 mg, 2.42 mmol) and diammonium carbonate (158 mg, 1.68 mmol) were reacted with 3-(4-fluoro-2-methyl-phenoxy) in methanol (15 mL). -6-Iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (536 mg, 1.05 mmol) was added at room temperature and the reaction was incubated at room temperature for 5 hours. It was stirred. The reaction mixture was concentrated to dryness under vacuum to give the crude product. Purification by FCC (Biotage Isolera, gradient elution 10-100% EtOAc:heptane) gave the title compound 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-5-methyl-N. -[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (89.0%) (520 mg, 0.856 mmol, 81%) was obtained as a light yellow solid. LC-MS: m/z 541 [M+H] ⁺ , (ESI+), RT = 0.75 METCR1410 typical 2 min.

Step 2: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(prop-1-yne-1- 1) Pyridazine-4-carboxamide: A solution of 1 M prop-1-yne (1 M in THF) (925 uL, 0.925 mmol) was reacted with 3-(4-fluoromethylene) in THF-anhydrous (0.5 mL). -2-methyl-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (50 mg, 0.0925 mmol), iodinated Copper (1+) (21 mg, 0.111 mmol) and 1,1'-bis(diphenylphosphanyl)ferrocene-dichloropalladium (1:1) (6.8 mg, 9.25 μmol) were added to a stirred N2 degassed mixture. And the reaction mixture was stirred in a pressure vial at room temperature for 20 hours. The reaction mixture was concentrated to dryness under vacuum to give the crude product. Purification by FCC (Biotage Isolera, SiO ₂ , gradient elution 0-30% EtOAc:heptane) gave the title compound, which was below the required purity spectrum and therefore the product was subjected to low pH preparative HPLC (standard method ) was purified. Product containing fractions were combined and solvent removed under vacuum to give the title compound 3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6- Prop-1-ynyl-pyridazine-4-carboxamide (100.0%) (15 mg, 0.0340 mmol, 37%) was obtained as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (t, J = 1.9 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.85 - 7.78 (m, 1H), 7.65 (t, J = 8.0 Hz) , 1H), 7.17 (dd, J = 8.9, 4.9 Hz, 1H), 7.05 (dd, J = 9.1, 3.0 Hz, 1H), 7.02 - 6.94 (m, 1H), 3.17 (s, 3H), 2.51 ( s, 3H), 2.19 (s, 3H), 2.16 (s, 3H). LC-MS: m/z 453.3 [M+H] ⁺ , (ESI+), RT = 2.78 MET-uPLC-AB-107 (7 min, high pH).

Example 23

Compound 1435: 3-(3,4-difluoro-2-methoxyphenoxy)-5,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxyx amides

Reagents & Conditions: a) 3-Chloro-5,6-dimethylpyridazine-4-carbonitrile, K ₂ CO ₃ , MeCN, 70°C, 18 hours b) Barium dihydroxide, H ₂ O, 80°C, 17 hours c) 1-bromo-3-(methylsulfanyl)benzene, disesium carbonate, Pd ₂ (dba) ₃ , XantPhos, 1-4-dioxane, 100°C, 4 hours d) PIDA, diammonium carbonate, MeOH , room temperature, 17 hours

Step 1: 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carbonitrile

3,4-difluoro-2-methoxy-phenol (1.00 g, 6.25 mmol), 3-chloro-5,6-dimethylpyridazine-4-carbonitrile (1.00 g, 5.97 mmol) in acetonitrile (8.5 mL) mmol) and dipotassium carbonate (1.25 g, 9.04 mmol) was stirred at 70°C for 18 hours. The reaction was filtered, washed with EtOAc (2 x), the filtrate was washed with brine, the organics were separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was then purified using the Biotage Isolena 4 flash purification system (Spa Duo 50 g, 0-45% EtOAc in heptane). Fractions containing the product were combined and evaporated under vacuum to afford the desired product 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carbonitrile (97.0%). ) (1.70 g, 5.66 mmol, 95%) was obtained as an off-white powder.

Step 2: 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carboxamide:

3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carbonitrile (97%, 200 mg, 0.666 mmol) was dissolved in water (6 mL). Dissolve and barium dioxide (560 mg, 3.27 mmol) was added. The resulting solution was stirred at 80°C for 17 hours. The solution was neutralized to pH 7 using 2M hydrochloric acid (aq) and the precipitate was filtered and washed with water (x 3) and EtOAc (x 2). The solid was dried in a vacuum oven overnight to give the desired product 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carboxamide (98.0%) (200%). mg, 0.634 mmol, 95%) was obtained as a white powder.

Step 3: 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: Anhydrous 1 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-pyridazine-4-carboxamide (180 mg, 0.582 mmol) in ,4-dioxane (3 mL) ), (1E,4E)-1,5-diphenyl in a degassed solution of 1-bromo-3-(methylsulfanyl)benzene (142 mg, 0.699 mmol) and disesium carbonate (567 mg, 1.74 mmol). Penta-1,4-dien-3-one - palladium (3:2) (27 mg, 0.0295 mmol) and (9,9-dimethyl-9H-xanthen-4,5-diyl)bis(diphenylphosphane) ) (34 mg, 0.0588 mmol) was added and the reaction was degassed for an additional 5 minutes. The vial was then sealed and the reaction was stirred at 100°C for 4 hours. The reaction mixture was then diluted with DCM and filtered through a phase separator. The filtrate was then washed with aqueous saturated sodium bicarbonate solution followed by brine. The organic extract was then dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography (10 g Spa Duo, eluting with 0-100% EtOAc in heptane). Fractions containing product (F41-54) were combined to give the desired product, 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfanylphenyl) ) Pyridazine-4-carboxamide (109 mg, 0.174 mmol, 30%) was obtained as a yellow solid.

Step 4: 3-(3,4-difluoro-2-methoxyphenoxy)-5,6-dimethyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxyx Amide: Diammonium carbonate (26 mg, 0.276 mmol) and bis(acetyloxy)(phenyl)-lambda~3~-iodan (PIDA) (130 mg, 0.404 mmol) were reacted with 3-(3) in methanol (2 mL). ,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (69%, 109 mg, 0.174 mmol) was added to the solution at room temperature, and the reaction was stirred at room temperature for 17 hours. The reaction mixture was concentrated to dryness under vacuum to give the crude product, which was purified by preparative HPLC (acidic initial elution method). Fractions containing the product were combined, evaporated under vacuum, and freeze-dried overnight to give the title compound, 3-(3,4-difluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-[ 3-(Methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (41 mg, 51%) was obtained as an off-white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H), 8.42 - 8.36 (m, 1H), 7.90 - 7.83 (m, 1H), 7.74 - 7.67 (m, 1H), 7.64 - 7.58 (m, 1H), 7.30 - 7.20 (m, 1H), 7.17 - 7.10 (m, 1H), 4.24 (s, 1H), 3.81 - 3.76 (m, 3H), 3.08 - 3.04 (m, 3H), 2.58 (s, 3H), 2.33 (s, 3H). m/z: 463.2 [M+H] ⁺ , (ESI+), RT = 2.46 LCMS Method 6.

Example 24

Compound 1436: 3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide

Reagents & Conditions: a) PdCl ₂ (dppf), PhB(OH) ₂ , Na ₂ CO ₃ , 1,4-dioxane, water, 90°C, 1 hour. b) LiOH, THF, water, room temperature, 2 days. c) HATU, 3-(methylsulfanyl)aniline, DIPEA, DMF, room temperature, 2 hours. d) PIDA, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature 16 hours,

Step 1: Methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylate: 1,1'-bis(diphenylphosphanyl) Ferrocene - Dichloropalladium (1:1) (17 mg, 0.0235 mmol) was dissolved in methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo in 1,4-dioxane (3.5 mL). N2 degassed stirred solution of -5-methyl-pyridazine-4-carboxylate (100 mg, 0.235 mmol), phenylboronic acid (43 mg, 0.353 mmol) and 2 M disodium carbonate (0.35 mL, 0.706 mmol) was added to. The reaction mixture was stirred in a pressure vial at 90° C. for 1 hour. The reaction mixture was diluted with EtOAc (30 mL), washed with water (3 x 20 ml) and brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product. The residue was purified by FCC (Biotage Isolera, SiO2, gradient elution 10-100% EtOAc:heptane) to give the title compound methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl. -6-Phenyl-pyridazine-4-carboxylate (85 mg, 0.226 mmol, 96%) was obtained as an off-white solid. LC-MS: m/z: 376 [M+H] ⁺ , (ESI+), RT = 0.92 METCR1704 (2 min uPLC gradient method for IPC).

Step 2: 3-(4-Cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylic acid: Lithium hydroxide (20 mg, 0.835 mmol) was dissolved in THF (2 mL) and methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylate (85 mg, 0.226 mmol) in water (0.25 mL) was added to the stirred solution. The reaction mixture was stirred at room temperature for 2 days. 1M aqueous HCl was added to the reaction mixture to pH ~2 and the reaction was extracted with EtOAc (3 x 20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylic. The acid (83.0%) (64 mg, 0.147 mmol, 65%) was obtained as an off-white solid, which was used as such in the next step. 100% molar yield was assumed. LC-MS: m/z 362 [M+H ^]+ , (ESI+), RT=0.65 METCR1704 (2 min uPLC gradient method for IPC).

Step 3: 3-(4-Cyano-2-methoxy-phenoxy)-5-methyl-N-(3-methylsulfanylphenyl)-6-phenyl-pyridazine-4-carboxamide: HATU ( 74 mg, 0.195 mmol) was dissolved in 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-phenyl-pyridazine-4-carboxylic acid (64 mg, 0.177 mmol) and N-ethyl-N-isopropyl-propan-2-amine (68 uL, 0.390 mmol) at room temperature, the reaction was stirred at room temperature for 5 minutes, and then 3-(methylsulfanyl ) Aniline (33 uL, 0.266 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (~50 mL) and washed with water (3 x 50 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Purification by FCC (Biotage Isolera, SiO ₂ gradient elution 10-80% EtOAc:heptane) gave the title compound 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-( 3-Methylsulfanylphenyl)-6-phenyl-pyridazine-4-carboxamide (76.0%) (79 mg, 0.124 mmol, 70%) was obtained as a yellow gum. LC-MS: m/z 483 [M+H] ⁺ , (ESI+), RT = 1.03 METCR1704 (2 min uPLC gradient method for IPC).

Step 4: 3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-phenylpyridazine-4-carboxamide : 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-phenyl-pyridazine-4-carboxamide, phenyl Iodonium di-acetate (PIDA) (121 mg, 0.377 mmol) and diammonium carbonate (25 mg, 0.262 mmol) were reacted with 3-(4-cyano-2-methoxy-phenoxy) in methanol (2.5 mL). -5-Methyl-N-(3-methylsulfanylphenyl)-6-phenyl-pyridazine-4-carboxamide (79 mg, 0.164 mmol) was added at room temperature and the reaction was incubated at room temperature for 16 hours. It was stirred. The reaction mixture was concentrated to dryness under vacuum to give the crude product. The residue was purified by low pH preparative HPLC (initial method). Product containing fractions were combined and solvent removed under vacuum to give the title compound 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6. -Phenyl-pyridazine-4-carboxamide (17 mg, 0.0327 mmol, 20%) was obtained as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.46 (t, J = 1.9 Hz, 1H), 8.00 - 7.95 (m, 1H), 7.85 - 7.80 (m, 1H), 7.66 (t, J = 8.0 Hz) , 1H), 7.59 - 7.49 (m, 6H), 7.48 - 7.39 (m, 2H), 3.83 (s, 3H), 3.17 (s, 3H), 2.41 (s, 3H). LC-MS: m/z 514 [M+H] ⁺ , (ESI+), RT = 2.78 min MET-uPLC-AB-107 (7 min, high pH).

Example 25

Compound 1437: 3-(4-Cyano-2-methoxy-phenoxy)-N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]-5-methyl-6-(trifluoro Romethyl)pyridazine-4-carboxamide

Reagents & Conditions: a) 3-Hydroxyazetidine hydrochloride, HATU, DIPEA, DCM. room temperature, 18 hours b) TFA, DCM, room temperature, 66 hours c) 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4- Carboxylic acid, HATU, DIPEA, DMF, room temperature, 16 hours

Step 1: tert-Butyl N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]carbamate: 3-[(tert-butoxycarbonyl)amino]benzoic acid in DCM (3 mL) To a mixture of (200 mg, 0.843 mmol), HATU (385 mg, 1.01 mmol) and DIPEA (442 uL, 2.53 mmol) was added 3-hydroxyazetidine.HCl (111 mg, 1.01 mmol). The reaction mixture was stirred at room temperature for 18 hours and then partitioned between DCM (10 mL) and water (10 mL). The layers were separated and the aqueous phase was extracted with DCM (2 x 10 mL). The combined organic portion was washed with brine (10 mL), dried using a phase separator, and concentrated under reduced pressure. The resulting crude product was purified by FCC (Biotage Isolera 4, 25 g Spa Duo, Lambda-all collection) using a gradient of 0-100% EtOAc/heptane followed by 0-20% MeOH/EtOAc to tert. -Butyl N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]carbamate (68.0%) (312 mg, 0.726 mmol, 86%) was obtained as a colorless gum. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 9.49 (s, 1H), 7.75 (s, 1H), 7.58 - 7.53 (m, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.18 ( dt, J = 7.7, 1.2 Hz, 1H), 5.74 (d, J = 6.3 Hz, 1H), 4.52 - 4.45 (m, 1H), 4.39 (t, J = 7.7 Hz, 1H), 4.27 - 4.18 (m , 1H), 4.01 - 3.96 (m, 1H), 3.80 - 3.71 (m, 1H), 1.48 (s, 9H). m/z: 293.1 [M+H] ⁺ , (ESI+), RT = 0.66 LCMS method M2.

Step 2: (3-aminophenyl)-(3-hydroxyazetidin-1-yl)methanone: tert-butyl N-[3-(3-hydroxyazetidin-1-car) in DCM (3 mL) To a solution of bornyl)phenyl]carbamate (68%, 312 mg, 0.726 mmol) was added trifluoroacetic acid (1.1 mL, 14.5 mmol). The reaction mixture was stirred at room temperature for 66 hours and then concentrated under reduced pressure. The resulting residue was co-evaporated with DCM-heptane (1:1) three times. The crude product was dissolved in MeOH (˜1 mL) and loaded onto a pre-wet SCX-2 cartridge (5 g, 25 mL). After washing with MeOH, the product was eluted _{with ˜2.5M NH 3} in MeOH. The product fractions were combined and concentrated under reduced pressure to obtain (3-aminophenyl)-(3-hydroxyazetidin-1-yl)methanone (80.0%) (138 mg, 0.574 mmol, 79%) as a light yellow opaque gum. It was obtained as. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.05 (t, J = 7.8 Hz, 1H), 6.83 - 6.79 (m, 1H), 6.69 (dt, J = 7.6, 1.2 Hz, 1H), 6.65 ( ddd, J = 8.0, 2.3, 0.9 Hz, 1H), 5.71 (br.s, 1H), 5.23 (br.s, 2H), 4.51 - 4.42 (m, 1H), 4.41 - 4.32 (m, 1H), 4.24 - 4.14 (m, 1H), 4.00 - 3.91 (m, 1H), 3.78 - 3.67 (m, 1H). m/z: 193.1 [M+H] ⁺ , (ESI+), RT = 0.23 LCMS method M2.

Step 3: 3-(4-Cyano-2-methoxy-phenoxy)-N-[3-(3-hydroxyazetidine-1-carbonyl)phenyl]-5-methyl-6-(trifluoro Romethyl)pyridazine-4-carboxamide: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine- in DMF (0.5 mL) (3-aminophenyl)-(3-hydroxyazetidine) in a mixture of 4-carboxylic acid (93%, 50 mg, 0.132 mmol), HATU (60 mg, 0.158 mmol) and DIPEA (46 uL, 0.263 mmol) -1-yl)methanone (80%, 38 mg, 0.158 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, then diluted with DMSO-MeCN-water (3:2:1, 1 mL), filtered, and purified by preparative HPLC (Purification Method 4). Product fractions were combined and concentrated under reduced pressure. The resulting residue was lyophilized from MeCN-water (1:1) to give 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(3-hydroxyazetidine-1-car Bornyl)phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (99.0%) (32 mg, 0.0595 mmol, 45%) was obtained as a white powder. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 8.00 (t, J = 1.9 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.40 (dt, J = 7.8, 1.3 Hz, 1H), 5.77 (s, 1H), 4.57 - 4.39 (m, 2H), 4.31 - 4.21 (m, 1H), 4.08 - 3.97 (m, 1H), 3.85 - 3.76 (m, 4H), 2.52 - 2.51 (m, 3H). m/z: 528.2 [M+H] ⁺ , (ESI+), RT = 2.71 LCMS method M4.

Example 26

Compound 1438: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(piperazine-1-carbonyl)phenyl]-6-(trifluoromethyl)pyri Minced-4-carboxamide

Reagents & Conditions: a) Fmoc-piperazine hydrochloride, HATU, DIPEA, DCM, room temperature, 66 hours b) 4M HCl in dioxane, room temperature, 4 hours c) 3-(4-cyano-2-methoxy- Phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid, HATU, DIPEA, DMF, room temperature, 16 hours d) Piperidine, MeCN, room temperature, 16 hours

Step 1: 9H-Fluoren-9-ylmethyl 4-[3-(tert-butoxycarbonylamino)benzoyl]piperazine-1-carboxylate: 3-[(tert-part) in DCM (7.5 mL) To a mixture of toxycarbonyl)amino]benzoic acid (500 mg, 2.11 mmol), HATU (962 mg, 2.53 mmol) and DIPEA (1.1 mL, 6.32 mmol) was added Fmoc-piperazine hydrochloride (872 mg, 2.53 mmol). did. The reaction mixture was stirred at room temperature for 66 hours and then partitioned between DCM (20 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with DCM (2 x 10 mL). The combined organic portion was washed with brine (20 mL), dried using a phase separator, and concentrated under reduced pressure. The resulting residue was purified by FCC (Biotage Isolera 4, 25 g Spa Duo, Lambda-all collection) using a 0-75% EtOAc/heptane gradient. The product fractions were combined and concentrated under reduced pressure to obtain 9H-fluoren-9-ylmethyl 4-[3-(tert-butoxycarbonylamino)benzoyl]piperazine-1-carboxylate (90.0%) (1.19 g, 2.03 mmol, 96%) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (d, J = 10.9 Hz, 1H), 7.92 - 7.86 (m, 2H), 7.86 - 7.82 (m, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.45 - 7.38 (m, 2H), 7.38 - 7.27 (m, 3H), 7.01 - 6.91 (m, 1H), 4.40 (d, J = 6.5 Hz, 1H), 4.32 - 4.22 (m, 1H), 3.63 - 3.45 (m, 3H), 3.30 - 3.14 (m, 3H), 2.77 - 2.55 (m, 2H), 1.66 - 1.55 (m, 1H), 1.51 - 1.45 (m, 9H). LC-MS: m/z 550.3 [M+Na] ⁺ , (ESI+), RT = 1.08 LCMS method M2.

Step 2: 9H-Fluoren-9-ylmethyl 4-(3-aminobenzoyl)piperazine-1-carboxylate: 9H-Fluoren-9-ylmethyl 4-[3-(tert-butoxycarbonyl Amino)benzoyl]piperazine-1-carboxylate (1.19 g, 2.26 mmol) was dissolved in 4M HCl in dioxane (25 mL). The reaction mixture was allowed to stir at room temperature for 4 hours and then concentrated under reduced pressure. Co-evaporate the solvent with DCM-heptane (1:1) to obtain 9H-fluoren-9-ylmethyl 4-(3-aminobenzoyl)piperazine-1-carboxylate hydrochloride (85.0%) (1.23 g, 2.25 g). mmol, 100%) was obtained as a pink solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.90 (d, J = 7.4 Hz, 2H), 7.63 (d, J = 7.4 Hz, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.8 Hz, 3H), 7.30 - 7.24 (m, 2H), 4.39 (d, J = 6.5 Hz, 2H), 4.32 - 4.24 (m, 1H), 3.73 - 3.64 (m, 2H), 3.55 - 3.43 (m, 4H), 3.35 - 3.11 (m, 4H). LC-MS: m/z 428.3 [M+H] ⁺ , (ESI+), room temperature = 0.88 LCMS method M2.

Step 3: 9H-Fluoren-9-ylmethyl 4-[3-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine -4-carbonyl]amino]benzoyl]piperazine-1-carboxylate: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(tri) in DMF (1 mL) 9H-fluorene-9- in a mixture of fluoromethyl)pyridazine-4-carboxylic acid (93%, 100 mg, 0.263 mmol), HATU (120 mg, 0.316 mmol) and DIPEA (138 uL, 0.790 mmol) Ilmethyl 4-(3-aminobenzoyl)piperazine-1-carboxylate;hydrochloride (85%, 172 mg, 0.316 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, then poured into water (10 mL) and extracted with EtOAc (15 mL). The organic phase was washed with water (2 x 10 mL) followed by 5% aqueous LiCl solution (2 x 10 mL), dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by FCC (Biotage Isolera 4, 10 g Spa Duo, Lambda-all collection) using a 0-100% EtOAc/heptane gradient. The product fractions were combined and concentrated under reduced pressure to give 9H-fluoren-9-ylmethyl 4-[3-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(tri Fluoromethyl)pyridazine-4-carbonyl]amino]benzoyl]piperazine-1-carboxylate (88.0%) (184 mg, 0.212 mmol, 81%) was obtained as a yellow glass. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.89 (s, 1H), 7.83 - 7.79 (m, 1H), 7.79 - 7.74 (m, 2H), 7.68 - 7.66 (m, 1H), 7.58 - 7.52 (m , 2H), 7.44 (t, J = 7.9 Hz, 1H), 7.42 - 7.38 (m, 2H), 7.38 - 7.36 (m, 2H), 7.34 - 7.29 (m, 2H), 7.27 (s, 1H), 7.11 (d, J = 7.7 Hz, 1H), 4.54 - 4.50 (m, 2H), 4.26 - 4.20 (m, 1H), 3.82 (s, 3H), 3.57 - 3.27 (m, 8H), 2.60 - 2.55 ( m, 3H). LC-MS: m/z 785.1 [M+Na] ⁺ , (ESI+), RT = 1.11 LCMS method M2.

Step 4: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(piperazine-1-carbonyl)phenyl]-6-(trifluoromethyl)pyri Minced-4-carboxamide: 9H-fluoren-9-ylmethyl 4-[3-[[3-(4-cyano-2-methoxy-phenoxy)-5- in acetonitrile (3 mL) A solution of methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]benzoyl]piperazine-1-carboxylate (184 mg, 0.241 mmol) was added to piperidine (95 uL, 0.965 mmol). and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (Purification Method 3). Product fractions were combined and concentrated under reduced pressure. The resulting residue was lyophilized from MeCN-water (1:1) to 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(piperazine-1-car). Bornyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (60 mg, 0.111 mmol, 46%) was obtained as an off-white powder. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 7.76 (t, J = 1.7 Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.67 (ddd, J = 8.2, 2.0, 0.9 Hz, 1H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.20 - 7.14 (m, 1H), 3.79 (s, 3H), 3.58 - 3.47 (m, 2H), 3.29 - 3.21 (m, 2H), 2.80 - 2.57 (m, 4H), 2.53 - 2.51 (m, 3H). Piperazine NH was not observed. LC-MS: m/z 541.2 [M+H] ⁺ , (ESI+), RT = 2.69 LCMS method M6.

Example 27

Compound 1439: 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(2-methoxyethylsulfamoyl)phenyl]-5-methyl-6-(trifluoromethyl)pyri Minced-4-carboxamide

Reagents & Conditions: a) 2-methoxyethaneamine, TEA, DCM, room temperature, 17 hours b) iron, ammonium chloride, EtOH, 90°C, 22 h c) 3-(4-cyano-2-methoxy-phenok Si)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid, EDC-HCl, pyridine, room temperature, 4 hours

Step 1: N-(2-methoxyethyl)-3-nitro-benzenesulfonamide: 2-methoxyethaneamine (94 uL, 1.09 mmol) and triethylamine (0.25 mL, 1.79 mmol) in DCM (4.5 mL) ) 3-nitrobenzenesulfonyl chloride (200 mg, 0.902 mmol) was added to the mixture. The reaction was stirred at room temperature for 17 hours. The reaction mixture was then poured into aqueous NaHCO ₃ and extracted with DCM (2×). The combined organic phases were filtered through a phase separator and concentrated under reduced pressure to give the desired product, N-(2-methoxyethyl)-3-nitro-benzenesulfonamide (99.0%) (216 mg, 0.822 mmol, 91%). Obtained as a brown oil.

Step 2: 3-Amino-N-(2-methoxyethyl)benzenesulfonamide: 3-Amino-N-(2-methoxyethyl)benzenesulfonamide (92.0%) (166 mg, in ethanol (6 mL) To a solution of 0.663 mmol, 81%), iron (459 mg, 8.22 mmol) and ammonium chloride (440 mg, 8.23 mmol) were added at room temperature. The resulting mixture was then stirred at 90°C for 22 hours. The reaction was filtered through Celite, washed with methanol (2 x 20 mL) and evaporated under reduced pressure to give the crude material. The residue was diluted with water (20 mL), extracted with ethyl acetate (3 x 20 mL) and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-amino-N-(2-methoxyethyl )Benzenesulfonamide (92.0%) (166 mg, 0.663 mmol, 81%) was obtained as an off-white powder.

Step 3: 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(2-methoxyethylsulfamoyl)phenyl]-5-methyl-6-(trifluoromethyl)pyri Minced-4-carboxamide: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxyl in pyridine (1 mL) 3- in a solution of acid (93%, 50 mg, 0.132 mmol) and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (1:1) (51 mg, 0.266 mmol). Amino-N-(2-methoxyethyl)benzenesulfonamide (92%, 66 mg, 0.264 mmol) was added. The mixture was stirred at room temperature for 4 hours. The solvent was removed (co-evaporated with MeCN) and the residue was purified by preparative HPLC (acidic initial elution method). Fractions containing the desired product were combined, evaporated, and freeze-dried overnight to give the desired product, 3-(4-cyano-2-methoxy-phenoxy)-N-[3-(2-methoxyethylsulfamoyl). Phenyl]-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (99.0%) (21 mg, 0.0368 mmol, 28%) was obtained as an off-white powder. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 8.29 - 8.25 (m, 1H), 7.88 - 7.82 (m, 1H), 7.82 - 7.79 (m, 1H), 7.76 - 7.73 (m, 1H), 7.64 - 7.58 (m, 2H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.52 - 7.49 (m, 1H), 3.79 (s, 3H), 3.32 - 3.28 (m , 2H, overlap with H ₂ O peak), 3.15 (s, 3H), 2.96 - 2.91 (m, 2H), 2.53 - 2.51 (m, 3H, overlap with DMSO peak). m/z: 566.1 [M+H] ⁺ , (ESI+), RT = 3.25 LCMS Method 4.

Compounds 1440-1445 listed in Table 11 were prepared by procedures similar to those described for compound 1439 using the appropriate acid and substituted aniline.

Table 11

Example 28

Compound 1446: 3-(4-Cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine- 4-Carboxamide

Reagents and conditions: a) LiOH, THF/H ₂ O room temperature; b) 3-(methylsulfanyl)aniline, HATU, DIEA, DMF, room temperature; c) phenyl iodonium diacetate, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature; d) 4-cyanophenyl)boronic acid, Pd(dppf)Cl ₂ .DCM, 2M Na ₂ CO ₃ , dioxane, 80°C.

Step 1: 3-(4-Cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid: Lithium hydroxide (37 mg, 1.55 mmol) was dissolved in THF ( 4 mL) and methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (200 mg, 0.470) in water (0.6 mL) mmol) was added to the solution at room temperature, and the reaction was stirred at room temperature for 2 days. 1M aqueous HCl was added to the reaction mixture to pH ~2 and the reaction was extracted with EtOAc (3 x 20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-car. Boxylic acid (91.0%) (193 mg, 0.428 mmol, 91%) was obtained, which was used as such in the next step. 100% molar yield was assumed. LC-MS: m/z 412 [M+H] ⁺ , (ESI+), RT = 0.55 min LCMS method 1.

Step 2: 3-(4-Cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide: N- [(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (196 mg, 0.516 mmol) was dissolved in 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid (193 mg, 0.469 mmol) and N-ethyl-N-isopropyl-propan-2-amine (180 uL, 1.03 mmol) at room temperature, the reaction was stirred at room temperature for 5 minutes, and then 3-(methylsulfanyl ) Aniline (87 uL, 0.704 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (~50 mL) and washed with water (3 x ~50 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Purified by FCC (Biotage Isolera, SiO ₂ gradient elution 10-50% EtOAc:heptane) to give 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl- N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (80.0%) (239 mg, 0.359 mmol, 77%) was obtained as a yellow gum. LC-MS: m/z 533 [M+H] ⁺ , (ESI+), RT = 1.01 min LCMS method 1.

Step 3: 3-(4-Cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide : Phenyl iodonium di-acetate (PIDA) (1044 mg, 3.24 mmol) and diammonium carbonate (212 mg, 2.25 mmol) were dissolved in 3-(4-cyano-2-methoxy-phenol) in methanol (22 mL). si)-6-iodo-5-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (750 mg, 1.41 mmol) was added at room temperature, and the reaction was stirred at room temperature for 16 minutes. Stirred for an hour. The reaction mixture was concentrated to dryness under vacuum to give the crude product. The residue was purified by FCC (Biotage Isolera SiO ₂ , gradient elution 10-100% EtOAc:heptane) 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N Purified by -[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (83.0%) (773 mg, 1.14 mmol, 81%). LC-MS: m/z 564 [M+H] ⁺ , (ESI+), RT = 0.71 min LCMS method 1.

Step 4: 3-(4-Cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine- 4-Carboxamide: 1,1'-bis(diphenylphosphanyl)ferrocene-dichloropalladium (1:1) (5.8 mg, 7.99 μmol) was dissolved in 3-(4) in 1,4-dioxane (1.8 mL). -Cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (45 mg, 0.0799 mmol) , 4-cyanophenyl)boronic acid (23 mg, 0.160 mmol) and 2 M disodium carbonate (2M aqueous) (120 uL, 0.240 mmol) were added to a stirred N ₂ degassed solution. The reaction mixture was stirred in a pressure vial at 80° C. for 2 hours. The reaction mixture was diluted with EtOAc (~3 mL) and washed with water (~2 ml). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. The residue was purified by high pH preparative HPLC (initial method). The product containing fractions were combined and the solvent was removed by lyophilization under vacuum to give 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-[ 3-(Methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (99.0%) (12 mg, 0.0224 mmol, 28%) was obtained as an off-white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 8.39 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.87 (d, J = 8.5 Hz, 1H) , 7.81 (d, J = 8.3 Hz, 2H), 7.74 - 7.67 (m, 2H), 7.65 - 7.59 (m, 1H), 7.58 - 7.53 (m, 1H), 7.49 (d, J = 8.2 Hz, 1H) ), 4.24 (s, 1H), 3.80 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). LC-MS: m/z 539.1 [M+H] ⁺ , (ESI+), RT = 2.60 LCMS method 7.

Compounds 1447-1457 listed in Table 12 were reacted with 3-(4-cyano-2-methoxy-phenoxy)- with the appropriate boronate(s) or boronic acid by a similar procedure as described for Step 4 of Example 28. It was prepared using 6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide coupling.

Table 12.

Example 29

Compound 1458: 3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(pyridin-2-yl)pyridazine -4-carboxamide

2-(tributylstannanyl)pyridine (82 mg, 0.224 mmol) was reacted with 3-(4-cyano-2-methoxy-phenoxy)-6-iodo- in 1,4-dioxane (2.5 mL). To a mixture of 5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (63 mg, 0.112 mmol) and CuI (2.1 mg, 0.0112 mmol) was added at room temperature and the reactants was stirred at room temperature for 5 minutes, then palladium-triphenylphosphan (1:4) (13 mg, 0.0112 mmol) was added, and the reaction was stirred at 110°C for 16 hours. The reaction mixture was diluted with EtOAc (~3 mL), washed with 1M aqueous KF, and the mixture was stirred at room temperature for 15 min and filtered through a pad of Celite. The layers were separated and the organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product. The residue was purified by low pH preparative HPLC (initial method). Product containing fractions were combined and the solvent was removed by lyophilization under vacuum. The crude product was diluted in CH ₃ CN (3 mL) and MP-TMT (200 mg, 0.132 mmol, 0.66 mmol/g) and stirred at room temperature for ˜16 hours. The product was diluted 1:1 in ACN:H ₂ O (~3 ml) and concentrated to dryness by lyophilization overnight to give 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N- [3-(Methylsulfonimidoyl)phenyl]-6-(2-pyridyl)pyridazine-4-carboxamide (98.0%) (21 mg, 0.0404 mmol, 36%) was obtained as an off-white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.79 - 8.65 (m, 1H), 8.47 (t, J = 1.9 Hz, 1H), 8.06 - 8.01 (m, 1H), 8.01 - 7.95 (m, 1H) , 7.88 - 7.80 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.58 - 7.50 (m, 2H), 7.49 - 7.38 (m, 2H), 3.83 (s, 3H), 3.18 (s) , 3H), 2.51 (s, 3H).

Compounds 1459-1464 listed in Table 13 were prepared with the appropriate substituted R-SnBu3 and 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5 by a similar procedure described for Example 29. It was prepared using -methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide.

Table 13

Example 30

Compound 1465: 3-(4-cyano-2-methylphenoxy)-N-(3-methanesulfonylphenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (br.s, 1H), 8.39 - 8.33 (m, 1H), 7.93 - 7.85 (m, 2H), 7.81 (dd, J = 8.4, 1.8 Hz , 1H), 7.77 - 7.66 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 3.24 (s, 3H), 2.56 - 2.53 (m, 3H), 2.17 (s, 3H). m/z: 491.0 [M+H] ⁺ , (ESI+), RT = 3.28 LCMS method 4.

Example 31

Compound 1466: 3-(4-fluoro-2-methylphenoxy)-5-methyl-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 8.34 - 8.29 (m, 1H), 7.77 (dt, J = 7.5, 1.8 Hz, 1H), 7.67 - 7.58 (m, 2H) ), 7.44 (s, 2H), 7.29 (dd, J = 8.9, 5.1 Hz, 1H), 7.24 (dd, J = 9.4, 3.0 Hz, 1H), 7.14 (td, J = 8.6, 3.2 Hz, 1H) , 2.53 - 2.51 (m, 3H), 2.12 (s, 3H). m/z: 485. 0 [M+H] ⁺ , (ESI+), RT = 3.97 LCMS Method 5.

Example 32

Compound 1467: 3-[2-fluoro-4-(trifluoromethoxy)phenoxy]-N-(3-methanesulfonylphenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4 -Carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (t, J = 1.9 Hz, 1H), 7.98 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.79 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 8.8 Hz, 1H), 7.37 (dd, J = 10.5, 2.4 Hz, 1H), 7.28 - 7.22 (m, 1H), 3.15 (s, 3H), 2.62 - 2.58 (m, 3H). 1 proton (NH) not observed. m/z: 554.0 [M+H] ⁺ , (ESI+), RT = 3.78 LCMS method 4.

Example 33

Compound 1468: N-(3-methanesulfonylphenyl)-5-methyl-3-{[2-methyl-6-(trifluoromethyl)pyridin-3-yl]oxy}-6-(trifluoromethyl ) Pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (t, J = 1.9 Hz, 1H), 7.97 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H) ), 7.81 - 7.76 (m, 2H), 7.69 (t, J = 8.0 Hz, 1H), 3.15 (s, 3H), 2.62 (q, J = 1.5 Hz, 3H), 2.47 (s, 3H). m/z: 535.5 [M+H] ⁺ , (ESI+), RT = 3.62 LCMS Method 4.

Example 34

Compound 1469: 3-[(6-bromo-2-methylpyridin-3-yl)oxy]-N-(3-methanesulfonylphenyl)-5-methyl-6-(trifluoromethyl)pyridazine- 4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.40 (t, J = 2.0 Hz, 1H), 7.96 (ddd, J = 8.1, 2.2, 1.1 Hz, 1H), 7.79 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.71 - 7.62 (m, 2H), 7.56 - 7.51 (m, 1H), 3.15 (s, 3H), 2.60 (q, J = 1.5 Hz, 3H), 2.37 (s, 3H). m/z: 545.3, 547.3 [M+H] ⁺ , (ESI+), RT = 3.44 LCMS method 4.

Example 35

Compound 1470: 3-[(3-fluoro-1-bicyclo[1.1.1]fentanyl)methoxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoro Romethyl)pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.41 (t, J = 2.0 Hz, 1H), 7.93 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.85 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 4.88 (s, 2H), 3.18 (s, 3H), 2.52 - 2.49 (m, 3H), 2.02 (d, J = 2.5 Hz, 7H). m/z: 473.4 [M+H] ⁺ , (ESI+), RT = 2.94 LCMS Method 4

Example 36

Compounds: 1471 and 1472

3-(4-Chloro-2-fluoro-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide The racemic mixture was separated using the following chiral separation conditions. Mobile phase: 85% heptane, 15% ethanol. Column: Chiralpak AS, 20 x 250 mm, 10 μm Flow rate: 18 mL/min. First eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.35 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.76 - 7.71 (m) , 2H), 7.64 (t, J = 7.9 Hz, 1H), 7.54 (t, J = 8.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 4.26 (s, 1H), 3.11 - 3.04 (m, 3H), 2.54 - 2.52 (m, 3H). m/z: 503.1, 505.1 [M+H] ⁺ , (ESI+), RT = 3.13 MET-uPLC-AB-101 (7 min, low pH) and second eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.36 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.76 - 7.70 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H) ), 7.54 (t, J = 8.6 Hz, 1H), 7.45 - 7.41 (m, 1H), 4.27 (s, 1H), 3.13 - 3.03 (m, 3H), 2.54 - 2.52 (m, 3H). m/z: 503.1, 505.1 [M+H] ⁺ , (ESI+), RT = 3.13 MET-uPLC-AB-101 (7 min, low pH).

Example 37

Compounds: 1473 and 1474

3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4 -The racemic mixture of carboxamides was separated using the following chiral separation conditions: Mobile phase 85:15 heptane:ethanol. Column Chiralpak AS, 20 x 250 mm, 10 μm. Flow rate (mL/min) 18. First eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.33 - 7.26 (m, 1H), 7.24 (ddd, J = 9.3, 5.3, 1.8 Hz, 1H), 4.26 (s, 1H), 3.87 - 3.76 (m, 3H), 3.11 - 2.99 (m, 3H), 2.54 - 2.52 (m, 3H). m/z: 516.9 [M+H] ⁺ , (ESI+), RT = 3.85 METCR1416 Hi res 7 min and second eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.34 - 7.26 (m, 1H), 7.24 (ddd, J = 9.3, 5.3, 1.9 Hz, 1H), 4.26 (s, 1H), 3.85 - 3.76 (m, 3H), 3.10 - 3.02 (m, 3H), 2.54 - 2.52 (m, 3H). m/z: 516.9 [M+H] ⁺ , (ESI+), RT = 3.86 METCR1416 Hi res 7 min.

Example 38

Compounds: 1475 and 1476

Compound 1475: 3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-N-(3-pyridyl)-6-(trifluoromethyl)pyridazine-4-car Voxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.24 (br.s, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.39 (dd, J = 4.7, 1.4 Hz, 1H), 8.16 ( ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.45 (dd, J = 8.1, 4.5 Hz, 1H), 7.34 - 7.20 (m, 2H), 3.84 - 3.78 (m, 3H), 2.54 - 2.52 ( m, 3H). m/z: 441.1 [M+H] ⁺ , (ESI+), RT = 3.00 MET-uPLC-AB-101 (7 min, low pH).

Compound 1476: 3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)-6-(trifluoro Romethyl)pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.48 (br.s, 1H), 8.72 (t, J = 1.6 Hz, 1H), 8.11 - 8.05 (m, 1H), 7.54 - 7.48 (m, 1H) ), 7.44 (dd, J = 8.4, 6.3 Hz, 1H), 7.36 - 7.20 (m, 2H), 3.85 - 3.78 (m, 3H), 2.54 - 2.52 (m, 3H). m/z: 457.1 [M+H] ⁺ , (ESI+), RT = 2.77 MET-uPLC-AB-101 (7 min, low pH).

Example 39

Compounds: 1477 and 1478

3-[2,3-difluoro-4-(trifluoromethoxy)phenoxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyri A racemic mixture of minced-4-carboxamides was separated using the following chiral separation conditions: 10% IPA, 90% CO ₂ , Chiralpak IC, 10 x 250 mm, 5 μm, 15 mL/min, sample in methanol. , IPA. First eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.38 (s, 1H), 8.34 (t, J = 1.8 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.70 - 7.59 (m, 2H), 7.58 - 7.49 (m, 1H), 4.26 (s, 1H), 3.12 - 3.03 (m, 3H), 2.56 - 2.53 (m, 3H). LC-MS: m/z 571.6 [M+H] ⁺ , (ESI+), RT = 4.24 LCMS method 5 and second eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.41 (s, 1H), 8.35 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.79 - 7.70 (m, 1H), 7.64 (t, J = 8.0 Hz, 2H), 7.57 - 7.50 (m, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.57 - 2.53 (m, 3H). LC-MS: m/z 571.1 [M+H] ⁺ , (ESI+), RT = 3.48 LCMS LCMS method M2.

Example 40

Compounds: 1479 and 1480

3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-car A racemic mixture of voxamides was separated using the following chiral separation conditions: Mobile phase 20% methanol: 80% CO ₂ Column Chiralpak IC, 10 x 250 mm, 5 μm flow rate (mL/min) 15. First eluting isomer ( S)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine- 4-carboxamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 8.33 (t, J = 2.0 Hz, 1H), 7.88 - 7.83 (m, 1H), 7.75 - 7.68 ( m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.3, 1.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 4.24 (s, 1H), 3.77 (s, 3H), 3.05 (d, J = 1.1 Hz, 3H), 2.51 - 2.50 (m, 3H). m/z: 506.3 [M+H] ⁺ , (ESI+), RT = 2.89 LCMS Method 6 and second eluting isomer (R)-3-(4-cyano-2-methoxyphenoxy)-5-methyl -N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 8.33 (t, J = 2.0 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.75 - 7.68 (m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.2, 1.8 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 4.24 (s, 1H), 3.77 (s, 3H), 3.05 (d, J = 1.1 Hz, 3H), 2.51 - 2.50 (m, 3H). m/z: 506.3 [M+H] ⁺ , (ESI+), RT = 2.89 LCMS Method 6.

Example 41

Compounds: 1481 and 1482

3-(4-chloro-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxyx A racemic mixture of amides was separated using the following chiral separation conditions: Chiral separation: 85% heptane, 15% ethanol, Chiralpak AS, 20 x 250 mm, 10 μm, 18 mL/min, sample in methanol, ethanol. First eluting isomer 1H NMR (500 MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 8.36 (t, J = 1.8 Hz, 1H), 7.89 - 7.85 (m, 1H), 7.75 - 7.70 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.33 - 7.29 (m, 2H), 7.10 (dd, J = 8.6, 2.3 Hz, 1H), 4.26 (s, 1H), 3.75 (s, 3H) ), 3.09 - 3.05 (m, 3H). 3H (1 Me) not observed - masked by DMSO signal. m/z: 503.1, 505.1 [M+H] ⁺ , (ESI+), RT = 3.06 LCMS method 4 and second eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 8.36 (t, J = 1.8 Hz, 1H), 7.90 - 7.85 (m, 1H), 7.75 - 7.70 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.10 (dd, J = 8.6, 2.3 Hz, 1H), 4.26 (s, 1H), 3.75 (s, 3H), 3.10 - 3.04 (m, 3H). 3H (1 CH ₃ ) not observed - masked by DMSO signal m/z: 503.1, 505.1 [M+H] ⁺ , (ESI+), RT = 3.13 LCMS method 4.

Example 42

Compound 1483: 3-[(2,6-dimethylpyridin-3-yl)oxy]-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6-( Trifluoromethyl)pyridazine-4-carboxamide

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.34 (s, 1H), 8.37 (t, J = 1.9 Hz, 1H), 8.13 (s, 1H), 7.89 - 7.84 (m, 1H), 7.77 - 7.71 (m, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 3.17 (s, 1H), 3.12 (s, 3H), 2.54 - 2.52 (m, 3H), 2.47 (s, 3H), 2.28 (s, 3H). m/z: 480.3 [M+H] ⁺ , (ESI+), RT = 2.74 LCMS Method 6.

Example 43

Compounds: 1484 and 1485

3-[(2,6-dimethylpyridin-3-yl)oxy]-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6-(trifluoro A racemic mixture of methyl)pyridazine-4-carboxamides was separated using the following chiral separation conditions: Mobile phase 70:30 heptane: IPA + 0.2% DEA column Cellulose-4, 21.2 x 250 mm, 5 μm flow rate (mL) /min) 9. First eluting isomer ¹ H NMR (500 MHz, CD ₃ OD) δ 8.33 (t, J = 2.0 Hz, 1H), 7.84 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.72 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H) , 3.05 (s, 3H), 2.47 (q, J = 1.5 Hz, 3H), 2.41 (s, 3H), 2.24 (s, 3H). m/z: 480.3 [M+H] ⁺ , (ESI+), RT = 2.55 LCMS method 6 and second eluting isomer ¹ H NMR (500 MHz, CD ₃ OD) δ 8.33 (t, J = 2.0 Hz, 1H) , 7.84 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.72 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 3.05 (s, 3H), 2.48 (q, J = 1.5 Hz, 3H), 2.41 (s, 3H), 2.24 (s, 3H) ). m/z: 480.3 [M+H] ⁺ , (ESI+), RT = 2.54 LCMS Method 6.

Example 44

Compound 1486: 3-(4-Chloro-3-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyri Minced-4-carboxamide

^1H NMR (400 MHz, DMSO) δ 11.35 (s, 1H), 8.36 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.64 ( t, J = 7.9 Hz, 1H), 7.57 (t, J = 8.6 Hz, 1H), 7.23 (d, J = 8.9 Hz, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.56 - 2.51 (m, 3H), 2.11 (d, J = 1.9 Hz, 3H). m/z: 517.1, 519.1 [M+H] ⁺ , (ESI+), RT = 3.30 LCMS Method 4

Example 45

Compounds: 1487 and 1488

3-(4-chloro-3-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine-4 -The racemic mixture of carboxamides was separated using the following chiral separation conditions: Mobile phase 15% methanol, 85% CO ₂ Column Chiralpak AS-H, 10 x 250 mm, 5 μm flow rate (mL/min) 15. Article 1 Eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.34 (s, 1H), 8.35 (t, J = 2.0 Hz, 1H), 7.90 - 7.81 (m, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.56 (t, J = 8.6 Hz, 1H), 7.22 (dd, J = 8.9, 1.6 Hz, 1H), 4.26 (s, 1H) , 3.07 (d, J = 1.1 Hz, 3H), 2.54 - 2.51 (m, 3H), 2.10 (d, J = 2.2 Hz, 3H). m/z: 517.4, 519.4 [M+H] ⁺ , (ESI+), RT = 3.42 LCMS method 4 and second eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.34 (s, 1H), 8.35 (t, J = 2.0 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.56 (t, J = 8.6 Hz, 1H), 7.22 (dd, J = 8.9, 1.6 Hz, 1H), 4.26 (s, 1H), 3.07 (d, J = 1.1 Hz, 3H), 2.54 - 2.52 (m, 3H), 2.12 - 2.08 (m, 3H). m/z: 517.4, 519.4 [M+H] ⁺ , (ESI+), RT = 3.42 LCMS method 4.

Example 46

Compound 1489: 3-(4-Chloro-3-fluoro-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl) Pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.34 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.93 - 7.84 (m, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.45 (dd, J = 9.0, 7.8 Hz, 1H), 7.28 (dd, J = 9.0, 2.0 Hz, 1H), 4.27 (s, 1H), 3.80 (d, J = 1.3 Hz, 3H), 3.08 (d, J = 0.8 Hz, 3H), 2.56 - 2.51 (m, 3H). m/z: 533.1, 535.1 [M+H] ⁺ , (ESI+), RT = 3.21 LCMS method 4.

Example 47

Compounds: 1490 and 1491

3-(4-chloro-3-fluoro-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridazine- The racemic mixture of 4-carboxamides was separated using the following chiral separation conditions: mobile phase 15% methanol, 85% CO ₂ column Chiralpak AS-H, 10 x 250 mm, 5 μm flow rate (mL/min) 15. First eluting isomer ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.33 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.44 (dd, J = 9.0, 7.7 Hz, 1H), 7.27 (dd, J = 9.0, 1.9 Hz, 1H), 4.26 (s, 1H) ), 3.79 (d, J = 1.3 Hz, 3H), 3.07 (d, J = 1.1 Hz, 3H), 2.54 - 2.52 (m, 3H). m/z: 533.1, 535.1 [M+H] ⁺ , (ESI+), RT = 3.22 LCMS method 4 and second eluting isomer ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.34 (s, 1H), 8.35 (t, J = 1.9 Hz, 1H), 7.92 - 7.83 (m, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.44 (dd, J = 9.0, 7.7 Hz, 1H), 7.27 (dd, J = 9.0, 2.0 Hz, 1H), 4.27 (s, 1H), 3.79 (d, J = 1.3 Hz, 3H), 3.07 (d, J = 1.1 Hz, 3H), 2.55 - 2.52 (m, 3H). m/z: 533.1, 535.1 [M+H] ⁺ , (ESI+), RT = 3.22 LCMS method 4.

Example 48

Compound 1492: 3-[4-(Cyclobutoxy)-2,3-difluoro-phenoxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoro Methyl)pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (t, J = 1.9 Hz, 1H), 7.98 (m, 1H), 7.86 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.11 (td, J = 8.7, 2.4 Hz, 1H), 6.90 - 6.81 (m, 1H), 4.80 (p, J = 6.9 Hz, 1H), 3.19 (s, 3H), 2.61 (d, J = 1.4 Hz) , 3H), 2.57 - 2.45 (m, 2H), 2.29 - 2.15 (m, 2H), 1.90 (m, 1H), 1.84 - 1.67 (m, 1H). m/z: 557.3 [M+H] ⁺ , (ESI+), RT = 3.63 LCMS Method 6.

Example 49

Compounds: 1493 and 1494

3-(4-cyclobutoxy-2,3-difluorophenoxy)-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6-(tri A racemic mixture of fluoromethyl)pyridazine-4-carboxamides was separated using the following chiral separation conditions: mobile phase 15% methanol, 85% CO ₂ column Chiralpak AS-H, 10 x 250 mm, 5 μm flow rate. (mL/min) 15. First eluting isomer ¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (t, J = 1.9 Hz, 2H), 8.02 - 7.94 (m, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.16 - 7.07 (m, 1H), 6.90 - 6.81 (m, 1H), 4.86 - 4.74 (m, 1H), 3.19 (s, 3H) ), 2.61 (d, J = 1.4 Hz, 3H), 2.57 - 2.45 (m, 2H), 2.29 - 2.15 (m, 2H), 1.91 (m, 1H), 1.84 - 1.68 (m, 1H). m/z: 557.2 [M+H] ⁺ , (ESI+), RT = 2.16 and second eluting isomer ¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (t, J = 1.9 Hz, 1H), 7.98 ( m, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.16 - 7.07 (m, 1H), 6.90 - 6.81 (m, 1H), 4.80 (p , J = 7.1 Hz, 1H), 3.19 (s, 3H), 2.63 - 2.58 (m, 3H), 2.51 (m, 2H), 2.29 - 2.15 (m, 2H), 1.90 (m, 1H), 1.76 ( m, 1H). m/z: 557.2 [M+H] ⁺ , (ESI+), RT = 3.81 chiral LC.

Example 50

Compound 1495: 3-[2-fluoro-4-(trifluoromethoxy)phenoxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyri Minced-4-carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.37 (s, 1H), 8.35 (t, J = 1.9 Hz, 1H), 7.89 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 7.77 - 7.69 (m, 2H), 7.69 - 7.61 (m, 2H), 7.44 - 7.37 (m, 1H), 4.26 (s, 1H), 3.10 - 3.06 (m, 3H), 2.55 - 2.52 (m, 3H). m/z: 553.1 [M+H] ⁺ , (ESI+), RT = 3.36 LCMS Method 4.

Example 51

Compounds: 1496 and 1497

3-[2-fluoro-4-(trifluoromethoxy)phenoxy]-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6-(tri A racemic mixture of fluoromethyl)pyridazine-4-carboxamides was separated using the following chiral separation conditions: Chiral separation: 10% methanol, 90% CO ₂ , Chiralpack IC, 10 x 250 mm, 5 μm; 15 mL/min, sample in methanol. First eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.37 (s, 1H), 8.38 - 8.32 (m, 1H), 7.92 - 7.85 (m, 1H), 7.76 - 7.70 (m, 2H) , 7.68 - 7.61 (m, 2H), 7.40 (d, J = 9.0 Hz, 1H), 4.26 (s, 1H), 3.07 (s, 3H), 2.55 - 2.52 (m, 3H). m/z: 553.1 [M+H] ⁺ , (ESI+), RT = 3.36 LCMS method 4 and second eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.37 (s, 1H), 8.37 - 8.33 (m, 1H), 7.91 - 7.86 (m, 1H), 7.77 - 7.69 (m, 2H), 7.69 - 7.61 (m, 2H), 7.40 (d, J = 9.1 Hz, 1H), 4.26 (s, 1H) ), 3.08 (s, 3H), 2.55 - 2.52 (m, 3H). m/z: 553.1 [M+H] ⁺ , (ESI+), RT = 3.36 LCMS Method 4.

Example 52

Compound 1498: 3-[(6-cyclobutoxy-2-methylpyridin-3-yl)oxy]-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl -6-(trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.40 (s, 1H), 8.37 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H) , 7.69 - 7.60 (m, 2H), 6.72 (d, J = 8.7 Hz, 1H), 5.10 (p, J = 7.2 Hz, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.45 - 2.36 (m, 2H), 2.22 (s, 3H), 2.05 (m, 2H), 1.78 (m, 1H), 1.64 (m, 1H). m/z: 536.2 [M+H] ⁺ , (ESI+), RT = 3.35 LCMS Method 4.

Example 53

Compounds: 1499 and 1500

3-((6-cyclobutoxy-2-methylpyridin-3-yl)oxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) A racemic mixture of pyridazine-4-carboxamides was separated using the following chiral separation conditions: 100% ethanol, Chiralpak AD-H, 20 x 250 mm, 5 μm, 9 mL/min. First eluting isomer ¹ H NMR (500 MHz, CD ₃ OD) δ 8.47 (t, J = 1.9 Hz, 1H), 7.98 (m, 1H), 7.89 - 7.83 (m, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.13 (p, J = 7.3 Hz, 1H), 3.19 (s, 3H), 2.61 (d, J = 1.3 Hz, 3H), 2.53 - 2.42 (m, 2H), 2.28 (s, 3H), 2.14 (m, 2H), 1.93 - 1.80 (m, 1H), 1.72 (m, 1H) . m/z: 536.2 [M+H] ⁺ , (ESI+), RT = 3.35 MET-uPLC-AB-101 (7 min, low pH LCMS method 4) and second eluting isomer ¹ H NMR (500 MHz, CD ³ OD) δ 8.47 (t, J = 1.9 Hz, 1H), 7.98 (m, 1H), 7.86 (m, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 5.14 (p, J = 7.2 Hz, 1H), 3.19 (s, 1H), 2.61 (d, J = 1.3 Hz, 3H), 2.54 - 2.43 ( m, 2H), 2.28 (s, 3H), 2.14 (m, 2H), 1.93 - 1.81 (m, 1H), 1.72 (m, 1H).

Example 54

Compound 1501: 3-[2,3-difluoro-4-(propan-2-yloxy)phenoxy]-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}- 5-Methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.37 (s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.78 - 7.70 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.29 - 7.20 (m, 1H), 7.18 - 7.11 (m, 1H), 4.71 (hept, J = 6.0 Hz, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.54 - 2.51 (m, 3H), 1.32 (d, J = 6.0 Hz, 6H). m/z: 545.3 [M+H] ⁺ , (ESI+), RT = 3.53 LCMS Method 6.

Example 55

Compounds: 1502 and 1503

3-(2,3-difluoro-4-isopropoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine A racemic mixture of -4-carboxamides was separated using the following chiral conditions: 80% heptane, 20% IPA, Chiralpak AS, 20 x 250 mm, 10 μm, 18 mL/min, sample in methanol, IPA. First eluting isomer ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.36 (br.s, 1H), 8.37 - 8.33 (m, 1H), 7.91 - 7.85 (m, 1H), 7.77 - 7.71 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.29 -7.20 (m, 1H), 7.18 - 7.10 (m, 1H), 4.71 (hept, J = 5.9 Hz, 1H), 4.27 (s, 1H) ), 3.10 - 3.05 (m, 3H), 2.55 - 2.51 (m, 3H), 1.32 (d, J = 6.0 Hz, 6H). LC-MS: m/z 545.3 [M+H] ⁺ , (ESI+), RT = 3.50 LCMS method 6 and second eluting isomer ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.36 (br.s, 1H ), 8.37 - 8.33 (m, 1H), 7.91 - 7.85 (m, 1H), 7.77 - 7.71 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.29 - 7.20 (m, 1H), 7.19 - 7.10 (m, 1H), 4.71 (hept, J = 5.9 Hz, 1H), 4.27 (s, 1H), 3.08 (s, 3H), 2.54 - 2.52 (m, 3H), 1.32 (d, J = 6.0 Hz, 6H). LC-MS: m/z 545.3 [M+H] ⁺ , (ESI+), RT = 3.51 LCMS method 6.

Example 56

Compound 1504: 3-(3-fluoro-4-methoxy-2-methylphenoxy)-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6 -(trifluoromethyl)pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (t, J = 2.0 Hz, 1H), 7.96 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 7.84 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.04 - 6.95 (m, 2H), 3.88 (s, 3H), 3.17 (s, 3H), 2.58 (q, J = 1.5 Hz, 3H), 2.07 (d, J = 2.2 Hz, 3H). m/z: 513.3 [M+H] ⁺ , (ESI+), RT = 3.12 LCMS Method 6.

Example 57

Compounds: 1505 and 1506

3-(3-fluoro-4-methoxy-2-methylphenoxy)-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6-(tri A racemic mixture of fluoromethyl)pyridazine-4-carboxamides was separated using the following chiral conditions: Mobile phase: 10% methanol: 90%CO ₂ Column: Chiralpak AS-H, 10 x 250 mm, 5 μm. Flow rate (mL/min) 15. First eluting isomer. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 8.34 (t, J = 1.8 Hz, 1H), 7.90 - 7.80 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.13 - 7.01 (m, 2H), 4.25 (s, 1H), 3.83 (s, 3H), 3.06 (d, J = 1.1 Hz, 3H), 2.51 - 2.50 (m, 3H), 2.01 (d, J = 2.2 Hz, 3H). m/z: 513.3 [M+H] ⁺ , (ESI+), RT = 3.13 LCMS method 6. And the second eluting isomer ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 8.34 ( t, J = 2.0 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.13 - 7.02 (m, 2H) ), 4.25 (s, 1H), 3.83 (s, 3H), 3.06 (d, J = 1.1 Hz, 3H), 2.51 - 2.50 (m, 3H), 2.01 (d, J = 2.1 Hz, 3H). m/z: 513.3 [M+H] ⁺ , (ESI+), RT = 3.13 LCMS Method 6.

Example 58

Compound 1507: N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-3-[(6-methoxy-2-methylpyridin-3-yl)oxy]-5-methyl- 6-(trifluoromethyl)pyridazine-4-carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ 8.45 (t, J = 2.0 Hz, 1H), 7.96 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.84 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.7 Hz, 1H), 3.91 (s, 3H), 3.17 (s, 3H), 2.59 (q, J = 1.6 Hz, 3H), 2.28 (s, 3H). m/z: 496.3 [M+H] ⁺ , (ESI+), RT = 2.96 LCMS Method 6.

Example 59

Compounds: 1508 and 1509

N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-3-[(6-methoxy-2-methylpyridin-3-yl)oxy]-5-methyl-6-( A racemic mixture of trifluoromethyl)pyridazine-4-carboxamides was separated using the following chiral conditions: Mobile phase: 85:15 heptane:ethanol Column: Chiralpak AS, 20 x 250 mm, 10 μm flow rate (mL) /min) 18. First eluting isomer ¹ H NMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.34 (t, J = 2.0 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.65 - 7.59 (m, 2H), 6.75 (d, J = 8.5 Hz, 1H), 4.25 (s, 1H), 3.84 (s, 3H), 3.06 (d, J = 1.1 Hz, 3H), 2.51 - 2.50 (m, 3H), 2.23 (s, 3H). m/z: 496.3 [M+H] ⁺ , (ESI ⁺ ), RT = 2.95 LCMS method 6 and second eluting isomer ¹ H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.34 (t , J = 2.0 Hz, 1H), 7.87 - 7.81 (m, 1H), 7.75 - 7.68 (m, 1H), 7.66 - 7.57 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H), 4.25 ( s, 1H), 3.84 (s, 3H), 3.06 (d, J = 1.2 Hz, 3H), 2.51 - 2.50 (m, 3H), 2.23 (s, 3H). m/z: 496.3 [M+H] ⁺ , (ESI ⁺ ), RT = 2.95 LCMS Method 6.

Example 60

Compound 1510: 3-[4-(difluoromethoxy)-2,3-difluoro-phenoxy]-5-methyl-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl) Pyridazine-4-carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 8.36 (t, J = 1.8 Hz, 1H), 7.89 (dd, J = 8.1, 1.1 Hz, 1H), 7.78 - 7.72 ( m, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.53 - 7.17 (m, 3H), 4.28 (s, 1H), 3.09 (s, 3H), 2.57 - 2.53 (m, 3H). m/z: 553.1 [M+H] ⁺ , (ESI+), RT = 3.18 LCMS Method 4.

Example 61

Compounds: 1511 and 1512

3-[4-(difluoromethoxy)-2,3-difluorophenoxy]-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6 A racemic mixture of -(trifluoromethyl)pyridazine-4-carboxamide was separated using the following chiral conditions: Mobile phase: 85:15 heptane:ethanol Column: Chiralpak AD-H, 20 x 250 mm, 5 μm Flow Rate (mL/min): 18 mL/min, sample in ethanol, methanol & acetonitrile. First eluting isomer ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.37 (s, 1H), 8.34 (t, J = 2.0 Hz, 1H), 7.88 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H ), 7.78 - 7.70 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.55 - 7.14 (m, 3H), 4.27 (d, J = 1.4 Hz, 1H), 3.08 (d, J = 1.1 Hz, 3H), 2.56 - 2.53 (m, 3H). m/z: 553.1 [M+H] ⁺ , (ESI+), RT = 3.19 LCMS method 4 and second eluting isomer ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 8.34 (t) , J = 2.0 Hz, 1H), 7.88 (ddd, J = 7.9, 2.2, 1.1 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.54 - 7.14 ( m, 3H), 4.27 (s, 1H), 3.08 (d, J = 1.2 Hz, 3H), 2.56 - 2.53 (m, 3H). m/z: 553.1 [M+H] ⁺ , (ESI+), RT = 3.19 LCMS Method 4.

Example 62

Compound 1513: 3-(4-carbamoylphenoxy)-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyri Minced-4-carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 8.33 (t, J = 2.0 Hz, 1H), 8.01 (s, 1H), 7.99 - 7.94 (m, 2H), 7.87 ( ddd, J = 8.1, 2.1, 1.1 Hz, 1H), 7.71 (ddd, J = 7.8, 1.8, 1.1 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.38 - 7.34 (m, 2H), 4.29 - 4.18 (m, 1H), 3.11 - 3.01 (m, 3H), 2.51 - 2.50 (m, 3H). m/z: 494.5 [M+H] ⁺ , (ESI+), RT = 2.19 LCMS Method 4.

Example 63

Compound 1514: 3-[2,6-difluoro-4-(trifluoromethoxy)phenoxy]-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5- Methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (400 MHz, CD3OD) δ 8.46 (t, J = 1.9 Hz, 1H), 7.96 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 7.85 (ddd, J = 7.9, 1.7, 1.0 Hz) , 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 3.18 (s, 3H), 2.61 (d, J = 1.4 Hz, 3H) The two NHs invisible. m/z: 571 [M+H] ⁺ , (ESI+), RT = 3.55 LCMS method 4.

Example 64

Compound 1515: 3-[3-fluoro-2-methyl-4-(trifluoromethoxy)phenoxy]-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5 -Methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.38 (br.s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.90 - 7.84 (m, 1H), 7.77 - 7.70 (m, 1H) ), 7.64 (t, J = 7.9 Hz, 1H), 7.56 (t, J = 8.8 Hz, 1H), 7.30 (dd, J = 9.1, 1.6 Hz, 1H), 4.26 (s, 1H), 3.07 (s , 3H), 2.55 -2.52 (m, 3H), 2.14 - 2.10 (m, 3H). m/z: 567.3 [M+H] ⁺ , (ESI+), RT = 3.66 LCMS Method 6.

Example 65

Compound 1516: 3-(3,4-difluoro-2-methoxyphenoxy)-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5H,6H,7H- Cyclopenta[c]pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 8.38 (t, J = 1.8 Hz, 1H), 7.88 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.70 ( dt, J = 7.8, 1.1 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.30 - 7.21 (m, 1H), 7.17 (ddd, J = 9.3, 5.3, 2.0 Hz, 1H), 4.24 (s, 1H), 3.82 - 3.75 (m, 3H), 3.12 - 3.02 (m, 7H), 2.22 - 2.12 (m, 2H). m/z: 475.3 [M+H] ⁺ , (ESI+), RT = 2.54 LCMS Method 6.

Example 66

Compound 1517: (S)-3-(4-Fluoro-2-methoxyphenoxy)-5-methoxy-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoro Methyl)pyridazine-4-carboxamide

Reagents & Conditions: a) 4-fluoro-2-methoxyphenol, K ₂ CO ₃ , acetonitrile, 70°C; b) NaI, CH ₃ COCl, acetonitrile, 0°C; c) Methyl difluoro(fluorosulfonyl)acetate, CuI, TBAI, DMF, 70°C;

d) 2,2,6,6-tetramethylpiperidine, n-BuLi (2.5M in hexane), 1-iodopyrrolidine-2,5-dione, THF, -78°C; e) 5.4 M NaOMe in MeOH, MeOH, 0° C. to room temperature; f) LiOH, THF:H ₂ O (8:2, v/v), room temperature; g) tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate; h) 4M HCl in dioxane, 1,4-dioxane.

Step 1: Methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate

4-fluoro-2-methoxyphenol (98%, 3.86 g, 26.6 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (5.25 g, 25.4 mmol) in acetonitrile (52 mL) and A mixture of K ₂ CO ₃ (5.26 g, 38.0 mmol) was stirred at 70° C. for 3.5 hours. The reaction mixture was cooled to room temperature, filtered through a phase separator, washed with DCM (3x 50 mL) and concentrated under vacuum. The compound was purified by FCC on silica using 0-100% EtOAc in heptane (on a Biotage Spa 100 g column, the compound was wet-loaded using DCM) and concentrated in vacuo to give methyl 6-chloro-3. -(4-Fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate (71.0%) (6.26 g, 56%) was obtained as a light yellow solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (s, 1H), 7.29 (dd, J = 8.8, 5.8 Hz, 1H), 7.14 (dd, J = 10.8, 2.9 Hz, 1H), 6.88 - 6.82 (m, 1H), 3.94 (s, 3H), 3.72 (s, 3H). LC-MA: m/z 313.0, 315.0 [M+H] ⁺ , (ESI+), RT = 0.88 LCMS method M2.

Step 2: Methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate

Methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate (84%, 6.19 g, 16.6 mmol) and iodination in acetonitrile (120 mL) Acetyl chloride (1.3 mL, 18.3 mmol) was added dropwise to a stirred solution of sodium (12.55 g, 83.1 mmol) at 0°C. The reaction was subsequently stirred at 0° C. for 1 hour. The reaction was diluted with EtOAc (200 mL) and washed with saturated aqueous Na ₂ CO ₃ (200 mL) and aqueous saturated sodium sulfite (50 mL). The aqueous layer was re-extracted with EtOAc (2x 200 mL), passed through a phase separator and concentrated under vacuum. The compound was purified by FCC on silica using 0-100% EtOAc in heptane (using a Biotage Spa 100 g column, the compound was wet-loaded using DCM) and concentrated in vacuo to give methyl 3-(4- Fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate (84.0%) (3.54 g, 44%) was obtained as a yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.25 (dd, J = 8.8, 5.8 Hz, 1H), 7.11 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 - 6.80 (m, 1H), 3.91 (s, 3H), 3.70 (s, 3H). LC-MS: m/z 405.1 [M+H] ⁺ , (ESI+), RT = 0.91 LCMS method M2.

Step 3: Methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: Methyl 3-(4-) in DMF (38 mL) Fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate (84%, 3.54 g, 7.36 mmol), iodoguri (2.11 g, 11.0 mmol), and tetrabutyl To a mixture of ammonium;iodide (1.09 g, 2.94 mmol), methyl difluoro(fluorosulfonyl)acetate (4.7 mL, 36.8 mmol) was added, and stirred at 70°C for 4 hours. The reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (3x 200 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum (high vacuum to remove DMF). The compound was purified by FCC on silica using 0-50% EtOAc in heptane (on a Biotage Spa 100 g column, the compound was wet-loaded using DCM) and concentrated in vacuo to give methyl 3-(4- Fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (93.0%) (2.52 g, 6.77 mmol, 92%) was obtained as a yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 7.33 (dd, J = 8.9, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 ( ddd, J = 8.9, 8.2, 2.9 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 3H). m/z: 347.0 [M+H]+, (ESI+), RT = 0.95 LCMS method M2.

Step 4: Methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate: THF-anhydrous (24 mL) To a stirred solution of 2,2,6,6-tetramethylpiperidine (0.68 mL, 4.03 mmol), butyllithium (2.5M in hexane) (1.1 mL, 2.69 mmol) was added dropwise at 0°C, and incubated for 30 minutes. It was stirred for a while. The reaction was cooled to -78°C and washed with methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluorocarbons) in THF-anhydrous (5 mL) at -78°C (over 40 min). Romethyl)pyridazine-4-carboxylate (93%, 500 mg, 1.34 mmol) was added dropwise and stirred at -78°C for 30 minutes. The reaction was cooled back to -78°C and 1-iodopyrrolidine-2,5-dione (332 mg, 1.48 mmol) in THF-anhydrous (5 mL) was added dropwise (over 20 min) at -78°C. , and stirred at this temperature for 30 minutes. The reaction was quenched with saturated aqueous NH4Cl (2 mL) at -78°C, allowed to warm to room temperature, and stirred for 30 minutes. The reaction mixture was poured into water (100 mL), extracted with EtOAc (3x 100 mL), passed through a phase separator and concentrated under vacuum. The compound was purified by FCC on silica using 0-50% EtOAc in heptane (on a Biotage Spa 10 g column, the compound was wet-loaded using DCM) and concentrated in vacuo to give methyl 3-(4- Fluoro-2-methoxy-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (82.0%) (216 mg, 0.375 mmol, 28%) as an orange solid. It was obtained as. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.32 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.85 (td, J = 8.5, 2.9) Hz, 1H), 4.02 (s, 3H), 3.73 (s, 3H). LC-MS: m/z 473.1 [M+H] ⁺ , (ESI+), RT = 1.03 LCMS method M2.

Step 5: Methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylate: Methanol-Anhydrous (3.3 mL) Heavy methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (82%, 216 mg, 0.375 mmol) To the stirred solution, 5.4 M NaOMe (0.069 mL, 0.375 mmol) in MeOH was added dropwise at 0°C. The reaction was subsequently allowed to stir at room temperature for 0.5 hours. The reaction was retreated with 5.4 M NaOMe in MeOH (0.035 mL, 0.188 mmol) at 0° C. and stirred for 0.5 h. The reaction was further retreated with 5.4 M NaOMe in MeOH (0.017 mL, 0.0938 mmol) and stirred at room temperature for 0.5 h. The reaction was quenched with saturated NH4Cl (aq.) (1 mL) and acidified to pH 1 with 2M HCl (aq.). The reaction mixture was concentrated under vacuum, poured into water (10 mL) and extracted with EtOAc (3x 10 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-80% MeOH in EtOAc (on a Biotage Spa 5 g column, the compound was wet-loaded using DCM) and concentrated in vacuo. methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylate (68.0%) (148 mg, 0.267 mmol , 71%) was obtained as a light yellow solid. LC-MS: m/z 377.1 [M+H] ⁺ , (ESI+), RT = 3.75 LCMS method 4.

Step 6: 3-(4-Fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid: THF (0.8 mL): Water ( Methyl 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylate (68%, 143 mg, in 0.2 mL) To the mixture (0.258 mmol), lithium hydroxide (12 mg, 0.517 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched to pH 1 with 2M HCl (aq), poured into water (10 mL) and extracted with EtOAc (3x 10 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-60% MeOH in EtOAc on silica (on a Biotage Spa 5 g column, the compound was wet-loaded with EtOAc) and vacuum Concentrated under 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid (82.0%) (71 mg, 0.161 mmol, 62%) was obtained as a light yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.25 (dd, J = 8.8, 5.8 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H), 6.84 (ddd, J = 8.9, 8.2 , 2.9 Hz, 1H), 4.17 (s, 3H), 3.73 (s, 3H). LC-MS: m/z 363.1 [M+H] ⁺ , (ESI+), RT = 3.03 LCMS method 4.

Step 7: tert-Butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine-4-car Boxamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate: 3-(4-fluoro-2-methyl-phenoxy)-5 in DMF-anhydrous (1.0 mL) -methoxy-6-(trifluoromethyl)pyridazine-4-carboxylic acid (82%, 95 mg, 0.225 mmol) in a stirred solution of N-ethyl-N-isopropyl-propan-2-amine at room temperature. (0.079 mL, 0.450 mmol) and HATU (103 mg, 0.270 mmol) followed by tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ^6- in DMF-anhydrous (0.5 mL). Sulfanylidene]carbamate (79 mg, 0.292 mmol) was added. The reaction was stirred at room temperature for 18 hours. The reaction was poured into water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was first purified by FCC on silica using 0-100% EtOAc in heptane (on a Biotage Spa 5 g column, the compound was wet-loaded using DCM), concentrated in vacuo and then again in heptane. Purified using 0-100% DCM followed by 0-100% EtOAc in DCM and purified on silica with 0-20% MeOH in EtOAc (on a Biotage Spa 10 g column, compounds were wet-loaded using DCM). Flush and concentrate under vacuum to obtain tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-6-(trifluoromethyl)pyridazine. -4-Carboxamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (88.0%) (74 mg, 0.106 mmol, 47%) was obtained as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.50 (s, 1H), 8.35 (s, 1H), 7.98 - 7.87 (m, 1H), 7.77 - 7.65 (m, 2H), 7.26 (dd, J = 8.9, 5.8 Hz, 1H), 7.12 (dd, J = 10.7, 2.9 Hz, 1H), 6.83 (td, J = 8.5, 2.9 Hz, 1H), 4.18 (s, 3H), 3.74 (s, 3H) , 3.39 (s, 3H), 1.21 (s, 9H). LC-MS: m/z 615.3 [M+H] ⁺ , (ESI+), RT = 0.84 LCMS method M2.

Step 8: (S)-3-(4-fluoro-2-methoxyphenoxy)-5-methoxy-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoro Methyl)pyridazine-4-carboxamide: tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)- in 1,4-dioxane (0.5 mL) of 5-methoxy-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (74 mg, 0.120 mmol) To the stirred solution was added 4 M HCl in dioxane (0.50 mL, 2.00 mmol) and the reaction was stirred at room temperature for 4 hours. The reaction was quenched with saturated Na ₂ CO ₃ (aq) (2 mL), poured into water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-80% MeOH in EtOAc on silica (on a Biotage Spa 5 g column, the compound was wet-loaded using DCM) and vacuum. It was concentrated under The compound was further purified by reverse phase FCC using 10-100% MeCN+0.1% formic acid+0.1% formic acid in water (on a C18 Biotage Spa 6 g column, using a sample preloaded with the MeOH solution). loaded), concentrated in vacuo to give 3-(4-fluoro-2-methoxy-phenoxy)-5-methoxy-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoro Methyl)pyridazine-4-carboxamide (99.0%) (9.0 mg, 14%) as a white solid, and (S)-3-(4-fluoro-2-methoxyphenoxy)-5-meth Toxy-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (99.0%) (18 mg, 29%) was obtained as a white solid. did. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.43 (s, 1H), 8.33 (t, J = 2.0 Hz, 1H), 7.87 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.73 ( dt, J = 8.0, 1.3 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.28 (dd, J = 8.8, 5.8 Hz, 1H), 7.13 (dd, J = 10.7, 2.9 Hz, 1H) ), 6.84 (td, J = 8.5, 2.9 Hz, 1H), 4.28 - 4.23 (m, 1H), 4.19 (s, 3H), 3.74 (s, 3H), 3.07 (d, J = 1.0 Hz, 3H) . LC-MS: m/z 515.1 [M+H] ⁺ , (ESI+), RT = 3.06, LC-MS method 4.

Example 67

Compound 1518: (S)-5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl ) Pyridazine-4-carboxamide

Reagents & Conditions: a) LiOH, THF/H ₂ O, room temperature; b) tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate, EDC, pyridine; c) Bromo(ethyl)magnesium (3M in Et ₂ O), THF, -78°C, NBS; d) DCM, TFA

Step 1: 3-(4-Fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid

THF (4.5 mL): Methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (500 mg, To the mixture (1.44 mmol), lithium hydroxide (173 mg, 7.22 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched to pH1 with 2M HCl (aq), poured into water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum to give 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (69.0% ) (509 mg, 73%) was obtained as a light yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 7.32 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 ( td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC_MS: m/z 333.0 [M+H] ⁺ , (ESI+), RT = 2.96 LCMS method 4.

Step 2: tert-Butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl )(methyl)(oxo) λ ⁶ -sulfanylidene)carbamate: 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxyl Acid (100 mg, 0.301 mmol), tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (98 mg, 0.361 mmol) and 3- A mixture of (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (69 mg, 0.361 mmol) was dissolved in pyridine (2 mL) and stirred at room temperature for 2 hours. The reaction was retreated with tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (20 mg, 0.072 mmol) and incubated at room temperature for 2 hours. It was stirred. The reaction was retreated with 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (14 mg, 0.072 mmol) and stirred at room temperature for 3 hours. The reaction was poured into water (30 mL) and extracted with DCM (3x 40 mL). The combined organic phases were passed through a phase separator, concentrated under vacuum and purified by FCC (on a Biotage Spa 10 g column, compounds were wet-loaded using DCM) using 0-100% EtOAc in heptane on silica. Purify and concentrate under vacuum to give tert-butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid. Amido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (95.0%) (175 mg, 0.284 mmol, 94%) was obtained as a light yellow solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.26 (s, 1H), 8.64 (s, 1H), 8.37 - 8.31 (m, 1H), 8.03 - 7.95 (m, 1H), 7.75 - 7.67 (m , 2H), 7.37 (dd, J = 8.8, 5.9 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.72 (s, 3H), 3.40 (s, 3H), 1.25 (s, 9H). LC-MS: m/z 585.2 [M+H] ⁺ , (ESI+), RT = 1.00 LCMS method M2.

Step 3: tert-Butyl (S)-((3-(5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carbox Amido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate:

tert-Butyl (S)-((3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-car in THF-anhydrous (1.5 mL) To a stirred solution of boxamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (72 mg, 0.123 mmol), bromo(ethyl)magnesium (3M in Et ₂ O) (0.21 mL, 0.616 mmol) was added at -78°C and stirred for 2.5 hours. The reaction was retreated with bromo(ethyl)magnesium (3M in Et ₂ O) (0.21 mL, 0.616 mmol) and stirred at -78°C for 1 hour. The reaction was quenched with methanol (0.40 mL, 9.85 mmol). NBS (39 mg, 0.222 mmol) was subsequently added to the reaction, allowed to warm to room temperature and stirred for 26 hours. The reaction was retreated with NBS (13 mg, 0.073 mmol, 0.6 equiv) and stirred at room temperature for 15.5 hours. The reaction was retreated with NBS (13 mg, 0.073 mmol, 0.6 equiv) and stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC on silica using 0-100% EtOAc in heptane, flushed with 0-20% MeOH in EtOAc (on a Biotage Spa 5 g column, the compound was wet-loaded using DCM). , concentrated under vacuum to give tert-butyl (S)-((3-(5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4- Carboxamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (60.0%) (66 mg, 52%) was obtained as a yellow oil. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.41 (s, 1H), 8.39 (t, J = 2.0 Hz, 1H), 7.93 (dt, J = 6.8, 2.2 Hz, 1H), 7.76 - 7.70 ( m, 2H), 7.31 (dd, J = 8.8, 5.9 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz, 1H), 3.75 (s) , 3H), 3.40 (d, J = 1.4 Hz, 3H), 2.85 (q, J = 7.3 Hz, 2H), 1.29 -1.24 (m, 3H), 1.23 (s, 9H). m/z: 613.3[M+H] ⁺ , (ESI+), RT = 0.91 LCMS method M3.

Step 4: (S)-5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl )Pyridazine-4-carboxamide: tert-butyl (S)-((3-(5-ethyl-3-(4-fluoro-2-methoxyphenoxy)-6- in DCM (0.8 mL) In a stirred solution of (trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (60%, 66 mg, 0.0646 mmol), TFA (0.048 mL, 0.646 mmol) was added dropwise and stirred at room temperature for 2 hours. The reaction was basified with saturated aqueous NaHCO ₃ solution (2 mL), poured into water (10 mL) and extracted with DCM (3x 20 mL). The combined organic phases were passed through a phase separator, concentrated under vacuum and purified by reverse phase using 10-100% MeCN+01% formic acid+0.1% formic acid in water (on a Biotage Spar C18 6g column, the compound was purified by MeOH (S)-5-ethyl-3-(4-fluoro-2-methyl), concentrated under vacuum, and lyophilized overnight. Toxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (90.0%) (14 mg, 38%) as white Obtained as a solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 8.36 (t, J = 2.0 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.77 - 7.69 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.9, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz) , 1H), 4.26 (s, 1H), 3.74 (s, 3H), 3.08 (d, J = 1.1 Hz, 3H), 2.84 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.5 Hz) , 3H). LC-MS: m/z 513.2 1 [M+H]+, (ESI+), RT = 3.04 LCMS method 4.

Example 68

Compound 1519: (S)-5-Cyclopropyl-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl ) Pyridazine-4-carboxamide

Reagents & Conditions: a) K ₂ CO ₃ , acetonitrile, 70°C; b) Acetyl chloride, NaI, acetonitrile; c) CuI, TBAI, methyl difluoro(fluorosulfonyl)acetate, DMF, 70°C; d) THF, 2,2,6,6-tetramethylpiperidine, n-BiLi (2.5 M in hexane), -78°C, 1-iodopyrrolidine-2,5-dione; e) Cyclopropylboronic acid, bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; Dichloropalladium, K ₂ CO ₃ , 100°C; f) LiOH, THF/H ₂ O, 40° C. 20 hours; g) Oxalyl chloride, tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate, DIEA, DMF, room temperature; h) DCM, TFA

Step 1: Methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate: 4-fluoro-2-methyl-phenol (79 mL) in acetonitrile A mixture of 5.05 g, 40.1 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (7.90 g, 38.2 mmol) and dipotassium carbonate (7.91 g, 57.2 mmol) was stirred at 70°C for 14.5 hours. . The reaction was cooled to room temperature, filtered, washed with DCM (2x 100 mL) and concentrated in vacuo. The compound was purified by FCC on silica using 0-50% EtOAc in heptane (on a Biotage Spa 350 g column, the compound was wet-loaded using DCM) and concentrated in vacuo to give methyl 6-chloro-3. -(4-Fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (9.12 g, 20.9 mmol, 55%) was obtained as a light yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (s, 1H), 7.26 -7.21 (m, 2H), 7.16-7.07 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H) ). LC-MS: m/z 297.0, 299.0 [M+H] ⁺ , (ESI+), RT = 0.93 LCMS method M2.

Step 2: Methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate: Methyl 6-chloro-3- in acetonitrile-anhydrous (34 mL) To a stirred solution of (4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (3.00 g, 10.1 mmol) and sodium iodide (15.16 g, 0.101 mol) was added acetonitrile-anhydride (34 A solution of acetyl chloride (0.79 mL, 11.1 mmol) in mL) was added dropwise over 30 min at 0-5°C. The reaction was subsequently stirred at 5°C for 30 minutes and then at room temperature for 2 hours. The reaction was retreated with acetyl chloride (0.10 mL, 1.41 mmol) at 0°C and stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (20 mL) and stirred for 5 minutes. Water (100 mL) was added and the resulting solution was extracted with EtOAc (3x 100 mL). The combined organic phases were washed with saturated aqueous sodium thiosulfate (2x 50 ml), passed through a phase separator, concentrated under vacuum and loaded on silica (on a Biotage Spar 200 g column, the compounds were wet-loaded using DCM). Purified by FCC using 0-100% EtOAc in heptane and concentrated in vacuo to give methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate. (95.0%) (2.19 g, 5.36 mmol, 53%) was obtained as a light yellow oil. LC-MS: m/z 389.0 [M+H] ⁺ , (ESI+), RT = 1.04 LCMS method M2.

Step 3: Methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: Methyl 3-(4-fluoro) in DMF (29.14 mL) Ro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (2.19 g, 5.64 mmol), iodoguri (1.62 g, 8.46 mmol), and tetrabutylammonium iodide ( To the mixture (836 mg, 2.26 mmol), methyl difluoro(fluorosulfonyl)acetate (3.6 mL, 28.2 mmol) was added and stirred at 70°C for 4 hours. The reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (3x 200 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum (high vacuum to remove DMF). The compound was purified by FCC on silica using 0-50% EtOAc in heptane (on a Biotage Spa 200 g column, the compound was wet-loaded using DCM) and concentrated in vacuo to give methyl 3-(4- Fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (76.0%) (1.49 g, 3.43 mmol, 61%) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 7.34 - 7.24 (m, 2H), 7.18 - 7.11 (m, 1H), 3.97 (s, 3H), 2.13 (s, 3H) ). LC-MS: m/z 331.1 [M+H] ⁺ , (ESI+), RT = 0.98 LCMS method M2.

Step 4: Methyl 3-(4-fluoro-2-methyl-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate: in THF-anhydrous (12 mL) To a stirred solution of 2,2,6,6-tetramethylpiperidine (0.58 mL, 3.45 mmol), butyllithium (2.5M in hexane) (0.92 mL, 2.30 mmol) was added dropwise at 0°C and incubated for 30 min. It was stirred. The reaction was cooled to -78°C and methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate in THF-anhydrous (12 mL). Both pre-cooled mixtures of (76%, 500 mg, 1.15 mmol) were transferred to the LiTMP mixture by cannula at -78°C. A pre-cooled mixture of 1-iodopyrrolidine-2,5-dione (259 mg, 1.15 mmol) in THF-anhydrous (6 mL) was added immediately thereafter at -78°C and incubated at this temperature for 30 min. It was stirred. The reaction was quenched with saturated NH ₄ Cl (aq) (1 mL) and allowed to warm to room temperature. The reaction was poured into water (30 mL), extracted with EtOAc (3x 50 mL) and the combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC on silica using 0-100% EtOAc in heptane, flushed with 0-60% MeOH in EtOAc (on a Biotage Spar 25g column, the compound was wet-loaded using DCM), Concentrate under vacuum to obtain methyl 3-(4-fluoro-2-methyl-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (85.0%) (342 mg, 0.637 mmol, 55%) was obtained as an orange solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.32 (dd, J = 9.0, 5.0 Hz, 1H), 7.26 (dd, J = 9.4, 3.1 Hz, 1H), 7.15 (td, J = 8.5, 3.2 Hz, 1H), 4.04 (s, 3H), 2.10 (s, 3H). LC-MS: m/z 457.0 [M+H] ⁺ , (ESI+), RT = 1.06 LCMS method M2.

Step 5: Methyl 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: 1,4-dioxane (1.8 mL): Methyl 3-(4-fluoro-2-methyl-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (75%) in water (0.2 mL) , 203 mg, 0.334 mmol), cyclopropylboronic acid (34 mg, 0.401 mmol), bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; A mixture of dichloropalladium (14 mg, 0.0167 mmol) and dipotassium carbonate (92 mg, 0.668 mmol) was degassed with nitrogen and heated to 100° C. for 3 hours. The reactant was mixed with bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; It was retreated with dichloropalladium (14 mg, 0.0167 mmol), degassed with nitrogen, and stirred at 100°C for 1 hour. The reactant was mixed with cyclopropylboronic acid (34 mg, 0.401 mmol), bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-1-yl]iron; dichloromethane; It was retreated with dichloropalladium (14 mg, 0.0167 mmol) and dipotassium carbonate (51 mg, 0.334 mmol), degassed with nitrogen, and stirred at 100°C for 4 hours. The reaction mixture was allowed to warm to room temperature, poured into water (20 mL) and extracted with DCM (3x 20 mL). The combined organic phases were passed through a phase separator, concentrated under vacuum and purified by FCC on silica using 0-100% EtOAc in heptane, flushed with 0-60% MeOH in EtOAc (Biotage Spa 10 g column). phase, the compound was wet-loaded using DCM) and concentrated in vacuo to give methyl 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine. -4-Carboxylate (81.0%) (114 mg, 0.249 mmol, 75%) was obtained as a yellow sticky oil. ¹ H NMR (500 MHz, DMSO-d ₆ -) δ 7.28 - 7.22 (m, 2H), 7.13 (td, J = 8.5, 3.5 Hz, 1H), 4.00 (s, 3H), 2.18 - 2.12 (m, 1H), 2.08 (s, 3H), 1.12 - 1.06 (m, 2H), 0.82 - 0.75 (m, 2H). LC-MS: m/z 371.2 [M+H] ⁺ , (ESI+), RT = 1.04 LCMS method M2.

Step 6: 5-Cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: THF (1 mL): Water (0.25 mL) mixture of methyl 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (113 mg, 0.305 mmol) To this, lithium hydroxide (15 mg, 0.610 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction was retreated with LiOH (29 mg, 1.22 mmol) and stirred at room temperature for 1 hour. The reaction was retreated with LiOH (29 mg, 1.22 mmol) and stirred at room temperature for 16 hours. The reaction was retreated with LiOH (29 mg, 1.22 mmol) and stirred at 40°C for 20 hours. The reaction was retreated with LiOH (29 mg, 1.22 mmol) and stirred at 60°C for 6.5 hours. The reaction was retreated with lithium hydroxide (29 mg, 1.22 mmol) and stirred at 40°C for 3 hours. The reaction mixture was acidified to pH 1 with 2M HCl (aq), poured into water (10 mL) and extracted with EtOAc (3x 10 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-80% MeOH in EtOAc on silica (on a Biotage Spa 5 g column, the compound was wet-loaded with EtOAc) and vacuum. Concentrated under 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (62 mg, 0.174 mmol, 57%) was obtained as an orange solid. LC-MS: m/z 357.2 [M+H] ⁺ , (ESI+), RT = 0.74 LCMS method M2.

Step 7: tert-Butyl N-[(S)-{3-[5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4- Amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate: 5-cyclopropyl-3-(4-fluoro-2-methyl-phenoxy)-6- in DCM (0.6 mL) To a stirred solution of (trifluoromethyl)pyridazine-4-carboxylic acid (92%, 52 mg, 0.134 mmol) was added N,N-dimethylformamide (2.1 uL, 0.0269 mmol) followed by oxalyl chloride (13 uL, 0.148 mmol) was added at room temperature under nitrogen. The reaction was stirred for 1 hour. Subsequently add tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (44 mg, 0.161 mmol) in DCM (0.2 mL) , then DIEA (47 uL, 0.269 mmol) was added and the reaction was stirred at room temperature for 1.5 hours. Water (2 mL) was added to the reaction and the reaction mixture was passed through a phase separator and rinsed with DCM (3x 3 mL). The combined organic phases were combined, concentrated in vacuo, purified by FCC on silica using 0-100% EtOAc in heptane, flushed with 0-60% MeOH in EtOAc (on a Biotage Spar 5 g column), and the compounds were purified by Wet-loaded using DCM), concentrated in vacuo to give tert-butyl N-[(S)-{3-[5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-6- (trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (94.0%) (79 mg, 0.122 mmol, 91%) as a white sticky solid. Obtained. m/z: 509.1 [M-Boc+H] ⁺ , (ESI+), RT = 0.99 LCMS method M2.

Step 8: (S)-5-Cyclopropyl-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl )Pyridazine-4-carboxamide: tert-butyl N-[(S)-{3-[5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)- in DCM (1.5 mL) To a stirred solution of 6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (94%, 79 mg, 0.122 mmol) was added TFA (0.091 mL, 1.22 mmol) was added dropwise and stirred at room temperature for 3 hours. The reaction was basified with saturated aqueous NaHCO ₃ solution (2 mL), poured into water (10 mL) and extracted with DCM (3x 20 mL). The combined organic phases are passed through a phase separator, concentrated under vacuum and purified on silica using 0-100% EtOAc in heptane (on a Biotage Spa 5 g column, wet-loading the compounds using DCM) Concentrate in vacuo and lyophilize overnight in 1:1 MeCN/water to give (S)-5-cyclopropyl-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfone Imidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (95.0%) (28 mg, 42%) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 8.29 (t, J = 2.0 Hz, 1H), 7.93 - 7.84 (m, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.29 - 7.21 (m, 2H), 7.13 (td, J = 8.5, 3.2 Hz, 1H), 4.26 (s, 1H), 3.12 - 3.03 (m) , 3H), 2.23 - 2.16 (m, 1H), 2.11 (s, 3H), 1.10 - 1.02 (m, 2H), 0.99 - 0.91 (m, 2H). LC-MS: m/z 509.1 [M+H] ⁺ , (ESI+), RT = 3.11 LCMS method 4.

Example 69

Compound 1520: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-phenyl-6-(trifluoromethyl) Pyridazine-4-carboxamide

The title compound was prepared by a similar procedure described for compound 1519 using the appropriate reagents. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 8.03 (t, J = 2.0 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.60 -7.55 (m, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.51 - 7.44 (m, 5H), 7.34 (dd, J = 8.9, 5.0 Hz, 1H), 7.28 (dd, J = 9.4, 3.2 Hz, 1H), 7.18 (td, J = 8.7, 3.3 Hz, 1H), 4.21 (s, 1H), 3.04 - 2.95 (m, 3H), 2.19 (s, 3H). m/z: 545.3 [M+H] ⁺ , (ESI+), RT = 3.37 LCMS Method 4.

Compound 1521: (S)-3-(4-fluoro-2-methylphenoxy)-5-(1-methyl-1H-pyrazol-4-yl)-N-(3-(S-methylsulfonimido 1) phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

The title compound was prepared by a similar procedure described for compound 1519 using the appropriate reagents. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 8.17 (t, J = 2.0 Hz, 1H), 8.06 (s, 1H), 7.74 - 7.67 (m, 2H), 7.65 ( s, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.31 (dd, J = 8.9, 5.0 Hz, 1H), 7.26 (dd, J = 9.4, 3.2 Hz, 1H), 7.16 (td, J) = 8.6, 3.2 Hz, 1H), 4.24 (s, 1H), 3.89 (s, 3H), 3.05 (s, 3H), 2.15 (s, 3H). m/z: 549.3 [M+H] ⁺ , (ESI+), RT = 2.88 LCMS method 4.

Example 70

Compound 1522: (S)-5-(Cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(tri Fluoromethyl)pyridazine-4-carboxamide

Reagents & Conditions: a) Cyclopropanamine, DIEA, acetonitrile, 50°C; b) LiOH, THF/H ₂ O, room temperature; c) TCFH, 1-methylimidazole, acetonitrile, tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate, room temperature; c) DCM, TFA, room temperature.

Step 1: Methyl 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: Acetonitrile-Anhydrous ( 2 mL) of methyl 3-(4-fluoro-2-methyl-phenoxy)-5-iodo-6-(trifluoromethyl)pyridazine-4-carboxylate (75%, 203 mg, 0.334 mmol), N-ethyl-N-(propan-2-yl)propan-2-amine (87 uL, 0.501 mmol) and cyclopropanamine (35 uL, 0.501 mmol) at 50°C for 3.5 hours. It was stirred. The reaction was combined with test, concentrated in vacuo, purified by FCC on silica using 0-100% EtOAc in heptane, flushed with 0-60% MeOH in EtOAc (on a Biotage Spar 5 g column) and the compounds were purified by Wet-loaded using DCM), concentrated under vacuum to give methyl 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine- 4-Carboxylate (75.0%) (182 mg, 0.354 mmol, 106%) was obtained as an orange solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.31 - 7.25 (m, 1H), 7.22 - 7.15 (m, 2H), 7.08 (td, J = 8.5, 3.2 Hz, 1H), 3.91 (s, 3H) ), 2.57 - 2.52 (m, 1H), 2.07 (s, 3H), 0.79 - 0.73 (m, 2H), 0.68 - 0.62 (m, 2H). LC-MS: m/z 386.2 [M+H]+, (ESI+), RT = 1.00 LCMS method M2.

Step 2: 5-(Cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: THF (1 mL): Methyl 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (75%) in water (0.3 mL) , 182 mg, 0.354 mmol), lithium hydroxide (17 mg, 0.709 mmol) was added, and the mixture was stirred at room temperature for 65 hours. The reaction mixture was quenched to pH1 with 2M HCl (aq), poured into water (10 mL) and extracted with EtOAc (3x 20 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC using 0-100% EtOAc in heptane followed by 0-80% MeOH in EtOAc on silica (on a Biotage Spa 5 g column, the compound was wet-loaded with EtOAc) and vacuum Concentrated under 5-(cyclopropylamino)-3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (86.0%) (164 mg) , 0.380 mmol, 107%) was obtained as a light yellow sticky oil. LC-MS: m/z 372.2 [M+H]+, (ESI+), RT = 0.78 LCMS method M2.

Step 3: tert-Butyl N-[(S)-{3-[5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine -4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate: 5-(cyclopropylamino)-3-(4-fluoro-2 in acetonitrile-anhydrous (0.5528 mL) -methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (78 mg, 0.210 mmol), tert-butyl N-[(S)-(3-aminophenyl)(methyl) To a stirred solution of oxo-λ ⁶ -sulfanylidene]carbamate (74 mg, 0.273 mmol) and 1-methylimidazole (NMI) (59 uL, 0.735 mmol), N-[chloro(dimethylamino)methyl Liden]-N-methylmethanaminium hexafluorophosphate (TCFH) (71 mg, 0.252 mmol) was added in a single portion and the reaction was stirred at room temperature for 15.5 hours. The reactant was mixed with 1-methylimidazole (NMI) (59 uL, 0.735 mmol) and N-[chloro(dimethylamino)methylidene]-N-methylmethanaminium hexafluorophosphate (TCFH) (71 mg, 0.252 mmol). ) and stirred at room temperature for 24 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC using 0-100% EtOAc in heptane, flushed with 0-60% MeOH in EtOAc (on a Biotage Spa 5 g column) and the compound was wetted using DCM and a few drops of EtOAc. loaded), concentrated in vacuo to give tert-butyl N-[(S)-{3-[5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoro Romethyl)pyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (138 mg, 0.153 mmol, 73%) was obtained as light yellow. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.23 (s, 1H), 8.38 - 8.32 (m, 1H), 7.96 - 7.86 (m, 1H), 7.70 - 7.62 (m, 2H), 7.23 - 7.13 (m, 2H), 7.13 - 7.03 (m, 2H), 3.36 (s, 3H), 2.68 - 2.65 (m, 1H), 2.09 (s, 3H), 1.17 (s, 9H), 0.74 - 0.69 (m , 2H), 0.63 - 0.54 (m, 2H). m/z: 624.2 1 [M+H] ⁺ , (ESI+), RT = 0.93 LCMS method M2.

Step 4: (S)-5-(Cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(tri Fluoromethyl)pyridazine-4-carboxamide: tert-butyl N-[(S)-{3-[5-(cyclopropylamino)-3-(4-fluoro-2) in DCM (2.7 mL) -methylphenoxy)-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (69%, 138 mg, 0.153 mmol) TFA (0.11 mL, 1.53 mmol) was added dropwise to the stirred solution, and stirred at room temperature for 3 hours. The reaction was basified with saturated aqueous NaHCO ₃ solution (2 mL), poured into water (10 mL) and extracted with DCM (3x 20 mL). The combined organic phases are passed through a phase separator, concentrated under vacuum and purified on silica using 0-100% EtOAc in heptane (on a Biotage Spa 5 g column, the compounds are wet-loaded using DCM), Concentrated under vacuum. The compounds were further purified by reverse phase FCC using 10-100% MeCN+0.1% formic acid+0.1% formic acid in water (on a C18 Biotage Spa 6 g column, sampler pre-loaded with compound solutions in MeOH). (S)-5-(cyclopropylamino)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-), concentrated under vacuum, and lyophilized overnight. Methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (100.0%) (44 mg, 0.0840 mmol, 55%) was obtained as a white solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 8.33 (t, J = 1.9 Hz, 1H), 7.87 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.13 - 7.03 (m, 2H), 4.22 (d, J = 1.3 Hz, 1H), 3.05 (d, J = 1.0 Hz, 3H), 2.73 - 2.66 (m, 1H), 2.10 (s, 3H), 0.75 - 0.68 (m, 2H), 0.66 - 0.58 (m, 2H). LC-MS: m/z 524.1 [M+H] ⁺ , (ESI+), RT = 2.79 LCMS method 4.

The following compounds were synthesized in the same manner as described above.

Compound 1523: (S)-5-(azetidin-3-ylamino)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)- 6-(trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 8.35 (t, J = 2.0 Hz, 1H), 7.94 - 7.85 (m, 1H), 7.75 - 7.67 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.23 - 7.12 (m, 2H), 7.08 (td, J = 8.5, 3.1 Hz, 1H), 4.56 - 4.44 (m, 1H), 4.27 (s, 1H) , 3.68 - 3.58 (m, 2H), 3.49 - 3.41 (m, 2H), 3.07 (s, 3H), 2.08 (s, 3H). m/z: 539.2 [M+H] ⁺ , (ESI+), RT = 1.71 LCMS Method 4.

Compound 1524: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-morpholino-6-(trifluoro Methyl)pyridazine-4-carboxamide

Example 71

Compound 1525: 3-(4-cyano-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6- (Trifluoromethyl)pyridazine-4-carboxamide

Reagents & Conditions: a) K ₂ CO ₃ , acetonitrile, 70°C; b) LiOH, THF/H ₂ O, room temperature; c) tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate, HATU, DIEA, DMF, room temperature; d) TFA, DCM.

Step 1: Methyl 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate: 4- in acetonitrile (11.5 mL) Hydroxy-3-methylbenzonitrile (650 mg, 4.88 mmol), methyl 3-chloro-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (94%, 1.20 g, 4.43 mmol) ) and K ₂ CO ₃ (920 mg, 6.66 mmol) was stirred at 70°C for 17 hours. The reaction was cooled to room temperature, filtered, and washed with EtOAc (60 mL). The filtrate was washed with water (60 mL) and brine (60 mL), the organic portion was separated, passed through a phase separator and concentrated under vacuum to give methyl 3-(4-cyano-2-methyl-phenoxy)- 5-Methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (90.0%) (1.68 g, 4.30 mmol, 97%) was obtained as an off-white powder. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.94 (d, J = 1.5 Hz, 1H), 7.82 (dd, J = 8.4, 2.1 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H) , 4.02 (s, 3H), 2.51 - 2.47 (m, 16H), 2.16 (s, 3H). m/z: 352.1 [M-BOC+H] ⁺ , (ESI+), RT = 0.94 LCMS Method 2.

Step 2: 3-(4-Cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid: THF (15 mL): Water (3 mL) ) of methyl 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylate (90%, 1.68 g, 4.30 mmol) To the solution, lithium hydroxide (236 mg, 9.46 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was diluted with EtOAc and the product was extracted with water (x 3). The pH of the aqueous phase was adjusted to 1 by dropwise addition of 1M HCl (aqueous). The aqueous layer was then extracted with EtOAc (3×), dried (MgSO ₄ ), filtered and concentrated in vacuo to give 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6- (Trifluoromethyl)pyridazine-4-carboxylic acid (99.0%) (1.48 g, 100%) was obtained as an off-white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.95 - 7.91 (m, 1H), 7.81 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 2.51 - 2.47 (m, 3H, overlaps with DMSO peak), 2.16 (s, 3H). m/z: 338.1 [M+H] ⁺ , (ESI+), RT = 2.67 LCMS Method 4.

Step 3: tert-Butyl N-[(S)-{3-[3-(4-cyano-2-methylphenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-amine do]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate: N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridine-3- yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (1000 mg, 2.63 mmol) was reacted with intermediate 3-(4-cyano-2-methyl-phenoxy)- in DMF-anhydrous (15 mL). of 5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid (740 mg, 2.19 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.77 mL, 4.41 mmol) was added to the solution. Then, tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (98%, 787 mg, 2.85 mmol) was added and the mixture was allowed to cool to room temperature. It was stirred for 18 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (3 x 50 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give tert-butyl N-[[3-[[3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluorocarbon Romethyl)pyridazine-4-carbonyl]amino]phenyl]-methyl-oxo-λ ⁶ -sulfanylidene]carbamate (48.0%) (1.95 g, 72%) was obtained as a brown oil. The material was used without further purification in subsequent reactions. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.44 (s, 1H), 8.40 - 8.36 (m, 1H), 7.95 - 7.87 (m, 2H), 7.85 - 7.80 (m, 1H), 7.78 - 7.69 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 3.40 (s, 3H), 2.69 (s, 3H), 2.17 (s, 3H), 1.22 (s, 9H). m/z: 490.1 [M-BOC+H] ⁺ , (ESI+), RT = 0.91 LCMS method 2.

Step 4: 3-(4-cyano-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6- (Trifluoromethyl)pyridazine-4-carboxamide: tert-butyl N-[(S)-{3-[3-(4-cyano-2-methylphenoxy)- in DCM (12 mL) In a solution of 5-methyl-6-(trifluoromethyl)pyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (48%, 1.95 g, 1.59 mmol) 2,2,2-trifluoroacetic acid (2.4 mL, 32.3 mmol) was added. The mixture was stirred at room temperature for 4 hours. The reaction was diluted with saturated NaHCO ₃ , extracted with DCM (3×), dried (MgSO ₄ ), filtered and concentrated to give a yellow oil. Purified by basic (0.1% NH ₃ ) reversed phase chromatography (Spar C18 60 g D Duo 30, 10-40% MeCN in H ₂ O, fractions 14 to 16 combined), evaporated and lyophilized over the weekend to give 3 -(4-cyano-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6-(trifluoro Methyl)pyridazine-4-carboxamide (141 mg, 0.282 mmol, 18%) was obtained as an off-white powder. The impure fraction was evaporated to a yellow oil (471 mg) and further purified by purification method 1. The material obtained first and the material obtained from purification method 1 were combined, freeze-dried overnight, and 3-(4-cyano-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo -λ ⁶ -sulfanyl]phenyl}-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide (463 mg, 60%) was obtained as a white powder. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (t, J = 1.9 Hz, 1H), 7.98 - 7.94 (m, 1H), 7.87 - 7.82 (m, 1H), 7.77 - 7.73 (m, 1H) , 7.71 - 7.64 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 3.17 (s, 3H), 2.62 - 2.59 (m, 3H), 2.23 (s, 3H). m/z: 490.2 [M+H] ⁺ , (ESI+), RT = 2.80 LCMS Method 4.

Example 72

Compound 1526: 3-(4-cyano-2-methylphenoxy)-N-{3-[(R)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6- (Trifluoromethyl)pyridazine-4-carboxamide

The title compound was reacted with 3-(4-cyano-2-methyl-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxylic acid and tert-butyl N-[(R)- (3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate was used to prepare by a similar reaction sequence as described for compound xx. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.44 (t, J = 1.9 Hz, 1H), 7.98 - 7.93 (m, 1H), 7.86 - 7.82 (m, 1H), 7.77 - 7.73 (m, 1H) , 7.71 - 7.64 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 3.17 (s, 3H, overlap with CD ₃ OD satellites), 2.63 - 2.58 (m, 3H), 2.23 (s, 3H) ). m/z: 490.2 [M+H] ⁺ , (ESI+), RT = 2.80 LCMS Method 4.

Example 73

Compound 1527: 3-(4-Cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl ) Pyridazine-4-carboxamide

Reagents & Conditions: 1-oxidopyridin-1-ium-3-amine hydrochloride, HATU, DIEA, DMF; b) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, 2M Na ₂ CO ₃ , 1,4-dioxane Pd(dppf) Cl ₂ .

Step 1: 3-(4-Cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)pyridazine-4 -Carboxamide: 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylic acid (64 mg, 0.156) in DMF (1.5 mL) mmol), HATU (71 mg, 0.187 mmol), and DIEA (0.082 mL, 0.467 mmol) were added 1-oxidopyridin-1-ium-3-amine;hydrochloride (25 mg, 0.171 mmol). The reaction mixture was stirred at 40° C. for 3 hours and then at room temperature overnight. LCMS analysis indicated that the reaction was complete. The mixture was diluted with ethyl acetate (10 mL) and washed with water (3x5 mL) and brine (5 mL). Dry (MgSO4), filter and concentrate to give an orange oil. The residue was purified by FCC (5 g, 0 to 100% MeOH in EA) to give 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-(1 -Oxidopyridin-1-ium-3-yl)pyridazine-4-carboxamide (80.0%) (32 mg, 33%) was obtained as an orange solid. m/z: 504.0 [M+H] ⁺ , (ESI+), RT = 0.62 min LCMS method 2.

Step 2: 3-(4-Cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl )Pyridazine-4-carboxamide: 2M Na ₂ CO ₃ (2M aqueous) (170 uL, 0.340 mmol) was dissolved in 4-(4,4,5,5-tetra) in 1,4-dioxane (2 mL). Methyl-1,3,2-dioxaborolan-2-yl)benzonitrile (29 mg, 0.115 mmol), 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5 -methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide (50 mg, 0.0888 mmol) and Pd(dppf)Cl ₂ (6.5 mg, 8.88 μmol) were added to the mixture. . The mixture was degassed with nitrogen for 5 minutes and then heated at 90°C for 6 hours. LCMS analysis indicated that the reaction was complete. The mixture was diluted with ethyl acetate (10 mL) and washed with water (5 mL) and brine (5 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give a brown oil. Purified by preparative HPLC (standard methods), 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-N-(1-oxidopyridine -1-ium-3-yl)pyridazine-4-carboxamide (99.0%) (10 mg, 18%) was obtained as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 9.06 (t, J = 1.9 Hz, 1H), 8.18 (m, 1H), 7.95 - 7.89 (m, 2H), 7.81 - 7.73 (m, 3H), 7.57 (dd, J = 8.6, 6.4 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.49 - 7.41 (m, 2H), 3.82 (s, 3H), 2.41 (s, 3H). m/z: 479.2 [M+H] ⁺ , (ESI+), RT = 2.36 LCMS Method 4.

Example 74

Compound 1528: 3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-N-{3-[(S)-imino(methyl)oxo- λ ⁶ -sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide

Reagents & Conditions: a) Potassium;(2,2-difluorocyclopropyl)-trifluoro-boranoid, Pd Amphos, 2M Na ₂ CO ₃ , 1,4-dioxane, 100°C; b) 1 M sodium trimethylsilanolate, THF; c) (S)-tert-Butyl N-[(3-aminophenyl)-methyl-oxo-λ ⁶ -sulfanylidene], HATU, DIEA, DMF, room temperature; d) TFA, DCM, room temperature

Step 1: Methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylate: 1, Methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-pyridazine-4-carboxylate (250 mg, 0.588 mmol) in 4-dioxane (2 mL) ), potassium;(2,2-difluorocyclopropyl)-trifluoro-boranoid (130 mg, 0.706 mmol) and 2 M disodium carbonate (882 uL, 1.76 mmol) were degassed with nitrogen. Pd Amphos (42 mg, 0.0588 mmol) was added and the solution was heated at 100°C overnight for 3 days. Additional boronate was not available for reprocessing. The solution was cooled and the material was purified using FCC (10 g silica, 0-100% EtOAc in heptane; direct loading reaction mixture). Clean fractions were evaporated under vacuum to yield methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxyl. Rate (45 mg, 0.120 mmol, 20%) was obtained as an off-white solid. m/z: 376.2 [M+H] ⁺ , (ESI+), RT = 0.87 min LCMS method 2.

Step 2: 3-(4-Cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylic acid: THF-anhydride (3 mL) of methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylate ( To a solution of 35 mg, 0.0933 mmol) was added 1 M sodium trimethylsilanolate (140 uL, 0.140 mmol) and the solution was stirred at ambient temperature for 3 hours. The solvent was removed under vacuum to give 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylic acid ( 75.0%) (45 mg, 0.0934 mmol, 100%) was obtained as a tan solid. The material was used without further purification in subsequent steps. m/z: 362.1 [M+H] ⁺ , (ESI+), RT = 0.61 min LCMS method 2.

Step 3: tert-Butyl N-[(S)-{3-[3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl pyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate: 3-(4-cyano-2-methoxy-phenoxy)-6-(2,2- Difluorocyclopropyl)-5-methyl-pyridazine-4-carboxylic acid (45 mg, 0.125 mmol), (S)-tert-butyl N-[(3-aminophenyl)-methyl-oxo-λ ⁶ A mixture of -sulfanylidene]carbamate (22 mg, 0.0830 mmol), HATU (35 mg, 0.0913 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.032 mL, 0.183 mmol) was dissolved in DMF. -Stirred in anhydrous (3.3672 mL) at ambient temperature for 4 hours. IPC indicated formation of the desired product. The mixture was purified directly using FCC (0-100% EtOAc followed by 0-20% MeOH in DCM, 10 g silica). Clean fractions were evaporated under vacuum to obtain tert-butyl N-[(S)-{3-[3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl). -5-Methylpyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (11 mg, 0.0142 mmol, 11%) was obtained as a white solid. m/z: 614.2 [M+H] ⁺ , (ESI+), RT = 0.87 min LCMS method 2.

Step 4 3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide: tert-butyl N-[[3-[[3-(4-cyano-2-methoxy-) in DCM (0.2423 mL) Phenoxy)-6-(2,2-difluorocyclopropyl)-5-methyl-pyridazine-4-carbonyl]amino]phenyl]-methyl-oxo-λ ⁶ -sulfanylidene]carbamate ( To a solution of 11 mg, 0.0179 mmol) was added TFA (0.2423 mL) and the solution was stirred at ambient temperature for 4 hours. IPC indicated formation of the desired product. The solvent was removed under a stream of nitrogen. Saturated aqueous sodium carbonate (1 mL) was added and the solution was extracted with DCM (3 x 1 mL). The combined organic portions were washed again with saturated sodium carbonate, passed through a phase separation frit, and the solvent was removed under vacuum to give a crude solid. Purification was attempted using a reversed phase standard acid gradient. Compound eluted at ~90% purity. Purification using standard FCC (10 g silica; 0-100% EtOAc in heptane followed by 0-30% MeOH in DCM) eluted the title compound and impurity ~10% MeOH. The solvent was removed under vacuum and the solid was lyophilized to give 3 3-(4-cyano-2-methoxyphenoxy)-6-(2,2-difluorocyclopropyl)-N-{3-[( S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide (90.0%) (8.3 mg, 0.0145 mmol, 81%) was obtained as an off-white solid. . ¹ H NMR (500 MHz, CD ₃ OD) δ 8.47 - 8.43 (m, 1H), 7.98 - 7.93 (m, 1H), 7.82 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.50 (s, 1H), 7.43 - 7.39 (m, 2H), 3.79 (s, 3H), 3.26 - 3.21 (m, 1H), 3.17 (s, 3H), 2.52 (s) , 3H), 2.48 - 2.39 (m, 1H), 2.04 - 1.97 (m, 1H). m/z: 514.2 [M+H]+, (ESI+), RT = 2.57 LCMS Method 4.

Example 75

Compound 1529: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(R)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6 -(4-methylphenyl)pyridazine-4-carboxamide

Reagents & Conditions: a) Pd(dppf)Cl ₂ .DCM, (4-methylphenyl)boronic acid, 2M Na ₂ CO ₃ , 1,4-dioane, 80°C; b) LiOH, THF/H ₂ O, room temperature; d) tert-butyl N-[(R)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate, HATU, DIEA, DMF; d) 4M HCl in dioxane, 1,4-dioxane, room temperature.

Step 1: Methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylate: 1,1'-bis(diphenyl Phosphanyl)ferrocene-dichloropalladium (1:1) (0.17 g, 0.235 mmol) was dissolved in methyl 3-(4-cyano-2-methoxy-phenoxy)-6 in 1,4-dioxane (12 mL). -Iodo-5-methyl-pyridazine-4-carboxylate (1.00 g, 2.35 mmol), (4-methylphenyl)boronic acid (0.64 g, 4.70 mmol) and 2 M disodium carbonate (2M aqueous) (3.5 mL, 7.06 mmol) of N2 was added to the degassed stirred solution. The reaction mixture was stirred in a pressure vial at 80° C. for 2 hours. LCMS analysis indicated that the reaction was complete. The mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL) and brine (15 mL). The organic portion was dried (MgSO4), filtered and concentrated to give a brown solid. Purified by FCC (25 g, 0 to 40% EA in heptane) to give methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4. -Carboxylate (77.0%) (1.20 g, 100%) was obtained as a light yellow solid. LCMS and ¹ H-NMR analysis indicated that this was the desired product with excess tolyl boronic acid. It was used directly in subsequent steps.

Step 2: 3-(4-Cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylic acid: THF (6 mL): Water (2 mL) ) in a solution of methyl 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylate (0.92 g, 2.35 mmol), Lithium hydroxide (0.13 g, 5.17 mmol) was added and the mixture was stirred at room temperature for 18 hours. LCMS analysis showed approximately 50% conversion. Additional lithium hydroxide (0.13 g, 5.17 mmol) in water (2 mL) was added and the mixture was stirred at room temperature for 18 hours. LCMS analysis showed approximately 75% conversion with 18% carboxamide at 215 nm. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 15 mL). The organic portion was concentrated to give 565 mg of a yellow semi-solid. The pH was then adjusted to 1 by dropwise addition of 2M HCl (aq.), the aqueous layer was extracted with EtOAc (2 x 15 mL), and the organics were concentrated to give 3-(4-cyano-2-methoxy-phenoxy )-5-Methyl-6-(p-tolyl)pyridazine-4-carboxylic acid (93.0%) (0.69 g, 73%) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (d, J = 1.8 Hz, 1H), 7.53 (dd, J = 8.2, 1.8 Hz, 1H), 7.49 - 7.40 (m, 3H), 7.32 ( d, J = 7.9 Hz, 2H), 3.79 (s, 3H), 2.38 (s, 3H), 2.30 (s, 3H). m/z: 376.2 [M+H] ⁺ , (ESI+), RT = 0.71 min LCMS method 2.

Step 3: tert-Butyl N-[(R)-{3-[3-(4-cyano-2-methoxyphenoxy)-5-methyl-6-(4-methylphenyl)pyridazine-4-amine [do]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate:

N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (0.79 g , 2.08 mmol) was dissolved in 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(p-tolyl)pyridazine-4-carboxylic acid ( 0.65 g, 1.73 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.60 mL, 3.46 mmol). After stirring the mixture at room temperature for 5 minutes, tert-butyl N-[(R)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (0.51 g, 1.90 mmol) was added. Added as a solution in DMF-anhydrous (4 mL). The mixture was stirred at room temperature for 18 hours. LCMS analysis indicated that the reaction was mostly complete. The mixture was diluted with ethyl acetate (30 mL) and washed with water (3 x 15 mL) and brine (15 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give a yellow foam. Purified by FCC (25 g, 0 to 100% EA in heptane) to give tert-butyl N-[(R)-{3-[3-(4-cyano-2-methoxyphenoxy)-5-methyl -6-(4-methylphenyl)pyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (90.0%) (0.90 g, 74%) was obtained as a light yellow foam. did. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.49 (t, J = 2.0 Hz, 1H), 8.02 - 7.95 (m, 1H), 7.78 (m, 1H), 7.70 (t, J = 8.0 Hz, 1H) ), 7.51 (m, 1H), 7.47 - 7.39 (m, 4H), 7.36 (d, J = 8.0 Hz, 2H), 3.83 (s, 3H), 3.35 (s, 3H), 2.43 (s, 3H) , 2.40 (s, 3H), 1.27 (s, 9H). m/z: 628.2 [M+H] ⁺ , (ESI+), RT = 0.94 min LCMS method 2.

Step 4: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(R)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6 -(4-Methylphenyl)pyridazine-4-carboxamide: tert-butyl N-[(R)-{3-[3-(4-cyano-) in 1,4-dioxane-anhydrous (8 mL) 2-methoxyphenoxy)-5-methyl-6-(4-methylphenyl)pyridazine-4-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (898 mg, 1.43 mmol) ) was added 4 m (18 mL, 71.5 mmol) of 4 M hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours. LCMS analysis indicated that the reaction was complete. The mixture was cooled to 0° C., diluted with ethyl acetate (20 mL), and the pH was adjusted to ˜9 using saturated NaHCO ₃ . Extracted with ethyl acetate (3 x 30 mL) and the organic portion was dried (MgSO ₄ ), filtered and concentrated to give an orange solid. Acidic (0.1% formic acid) reverse phase chromatography (Spar C18 30 g D Duo, 10% MeCN in H ₂ O 2 CV, 10-25% MeCN in H ₂ O 2 CV, 25-40% MeCN in H ₂ O 12 CV , 40% MeCN in H ₂ O 8 CV, then 40-100%® 6CV) to give a white solid (~480 mg), which was dissolved in MeCN (20 mL) and purified by Si TMT (TCI Chemicals ( TCI chemicals (TCI chemicals), 0.5 mmol/g, 1.41 g) were scavenged at room temperature for 30 minutes. The mixture was filtered, concentrated and freeze-dried to obtain 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(R)-imino(methyl)oxo-λ ⁶ -sulfanyl. ]phenyl}-5-methyl-6-(4-methylphenyl)pyridazine-4-carboxamide (100.0%) (435 mg, 58%) was obtained as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.46 (t, J = 2.0 Hz, 1H), 7.97 (m, 1H), 7.83 (m, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.47 - 7.39 (m, 4H), 7.36 (d, J = 7.8 Hz, 2H), 3.83 (s, 3H), 3.17 (s, 3H), 2.43 (s) , 3H), 2.41 (s, 3H). m/z: 528.2 [M+H] ⁺ , (ESI+), RT = 2.88 LCMS Method 4.

Example 76

Compound 1530: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6 -(4-methylphenyl)pyridazine-4-carboxamide

The title compound was prepared using a similar procedure as above but using tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate. By this route, 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl-6 -(4-Methylphenyl)pyridazine-4-carboxamide (0.52 g, 0.984 mmol) was obtained as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.46 (t, J = 2.0 Hz, 1H), 8.01 - 7.93 (m, 1H), 7.83 (m, 1H), 7.65 (t, J = 8.0 Hz, 1H) ), 7.51 (m, 1H), 7.47 - 7.40 (m, 4H), 7.36 (d, J = 8.0 Hz, 2H), 3.83 (s, 3H), 3.17 (s, 3H), 2.43 (s, 3H) , 2.41 (s, 3H). m/z: 528.2 [M+H] ⁺ , (ESI+), RT = 2.88 LCMS Method 4.

Example 77

Compound 1531: (R)-3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl) Phenyl) pyridazine-4-carboxamide

Reagents & Conditions: a) Pd(dppf)Cl ₂ .DCM, (4-cyanophenyl)boronic acid, 2M Na ₂ CO ₃ , 1,4-dioxane, 80°C; b) LiOH, THF/H ₂ O, room temperature; c) tert-butyl N-[(R)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate, HATU, DIEA, DMF, d) 4M HCl in dioxane, 2- Propanol, 1,4-dioxane.

Step 1: Methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-pyridazine-4-carboxylate: Pd(dppf)Cl ₂ .DCM (1:1) (172 mg, 0.235 mmol) was dissolved in methyl 3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5 in 1,4-dioxane (40 mL). -Methyl-pyridazine-4-carboxylate (1000 mg, 2.35 mmol), (4-cyanophenyl)boronic acid (691 mg, 4.70 mmol) and 2 M disodium carbonate (2M aqueous) (3.5 mL, 7.06 mmol) of N ₂ was added to the degassed stirred solution. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was diluted with EtOAc (~80 mL) and washed with water (~20 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Purified by FCC (Biotage Isolera, SiO ₂ , gradient elution 10-100% EtOAc:heptane) to give methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyano Phenyl)-5-methyl-pyridazine-4-carboxylate (92.0%) (891 mg, 87%) was obtained as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (dd, J = 16.0, 8.2 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.39 - 7.31 (m, 2H), 7.26 - 7.19 ( m, 1H), 4.05 (s, 3H), 3.80 (s, 3H), 2.37 (s, 3H). m/z: 401 [M+H] ⁺ , (ESI+), RT = 0.87 LCMS method 2.

Step 2: 3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine-4-carboxylic acid: Lithium hydroxide (117 mg, 4.90 mmol) Methyl 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-pyridazine- in THF-anhydrous (19 mL) and water (2.5 mL) A solution of 4-carboxylate (891 mg, 2.23 mmol) was added at room temperature and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated to low volume (THF removed), diluted in water (~20 ml) and washed with TBME (~20 ml). The basic aqueous phase was cooled to 0° C. and acidified to pH 2-3 by addition of 2M aqueous HCl. The organic phase was extracted with EtOAc (3 x 50 ml). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude product 3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine- 4-Carboxylic acid (91.0%) (674 mg, 1.745 mmol) was obtained, which was used as such in the next step. 100% molar yield was assumed.

Step 3: tert-Butyl (R)-((3-(3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine-4-car Boxamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate:

N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (HATU) (730 mg, 1.92 mmol) was dissolved in 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl-pyridazine-4- in DMF (6 mL). To a mixture of carboxylic acid (674 mg, 1.74 mmol) and N-ethyl-N-isopropyl-propan-2-amine (670 uL, 3.84 mmol) was added at room temperature and the reaction was stirred at room temperature for 5 minutes. , add a solution of tert-butyl N-[(R)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (472 mg, 1.74 mmol) in DMF (6 mL) , the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (~50 mL) and washed with water (3 x ~50 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Purified by FCC (Biotage Isolera, SiO ₂ gradient elution 10-50% EtOAc:heptane) to give tert-butyl (R)-((3-(3-(4-cyano-2-methoxyphenoxy )-6-(4-cyanophenyl)-5-methylpyridazine-4-carboxamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (887 mg, 80% ) was obtained as a yellow gum. The material was used without further purification in subsequent steps.

Step 4: (R)-3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methyl-N-(3-(S-methylsulfonimidoyl) Phenyl)pyridazine-4-carboxamide: 4 M hydrogen chloride (4M in dioxane) (12 mL, 46.8 mmol) was reacted with tert-butyl in 1,4-dioxane (5.5 mL) and 2-propanol (5.5 mL). (R)-((3-(3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-5-methylpyridazine-4-carboxamido)phenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (598 mg, 0.936 mmol) was added to the solution. The mixture was stirred at room temperature for 4 hours. The reaction was cooled to 0°C and diluted with EtOAc, -50 ml. It was basified to pH9 by adding saturated aqueous NaHCO3 dropwise. The aqueous phase was extracted with EtOAc (3 x 50 mL). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo to give the crude desired product, which was purified in low pH reverse phase Biotage 2 , 10-25% MeCN in H ₂ O 2 CV, 25-40% MeCN in H ₂ O 12 CV, 40% MeCN in H ₂ O 8 CV, then 40-100% ACN 6CV). The product-containing fractions were combined and the solvent removed under vacuum to yield 381 mg of the desired product as a white solid, which was diluted in ACN (30 ml) and purified at room temperature with Si TMT, TCI Chemicals, 0.5 mmol/g, 1.85 g. Scavenged for 30 minutes. The scavenger was filtered through a Douche tube and concentrated to dryness under vacuum. The residue was diluted 3:2 water:ACN (10 ml) and lyophilized overnight to obtain (R)-3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl). -5-Methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide (100.0%) (331 mg, 66%) was obtained. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 8.39 (s, 1H), 8.02 (d, J = 8.3 Hz, 2H), 7.87 (d, J = 8.6 Hz, 1H) , 7.81 (d, J = 8.3 Hz, 2H), 7.75 - 7.68 (m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.2, 1.7 Hz, 1H), 7.49 ( d, J = 8.2 Hz, 1H), 4.25 (s, 1H), 3.80 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). m/z: 539.2 [M+H] ⁺ , (ESI+), RT = 2.67 LCMS Method 6.

Example 78

Compound 1532: 3-(4-cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulphenyl panyl]phenyl}-5-methylpyridazine-4-carboxamide.

The title compound was prepared in a manner similar to that described for Example 77, Compound 1531, except that 3-(4-cyano-2-methoxy-phenoxy)-6-(4-cyanophenyl)-5-methyl- Using pyridazine-4-carboxylic acid and tert-butyl N-[(S)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate, finally 3-(4- Cyano-2-methoxyphenoxy)-6-(4-cyanophenyl)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-methyl Pyridazine-4-carboxamide (279 mg, 0.513 mmol) was obtained. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 8.40 (s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.5 Hz, 1H) , 7.81 (d, J = 8.3 Hz, 2H), 7.75 - 7.68 (m, 2H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.2, 1.7 Hz, 1H), 7.49 ( d, J = 8.2 Hz, 1H), 4.26 (s, 1H), 3.80 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H). 0.3WT% ACN. m/z: 539.0 [M+H] ⁺ , (ESI+), RT = 2.67 MET-uPLC-AB-101 (7 min, low pH).

Compounds 1533 to 1537 were prepared using the relevant route, but using the appropriate commercially available boronic acid/ester/BF3 salt for the Suzuki step and the appropriate chiral intermediate tert-butyl N-[(S) for the related chiral sulfoximine product. -(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene]carbamate or tert-butyl N-[(R)-(3-aminophenyl)(methyl)oxo-λ ⁶ -sulfanylidene ]Prepared using carbamate.

Compound 1533: 3-(4-cyano-2-methoxyphenoxy)-6-[4-(difluoromethyl)phenyl]-N-{3-[(S)-imino(methyl)oxo- λ ⁶ -sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ )) δ 11.29 (s, 1H), 8.40 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.83 - 7.68 (m, 6H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.2, 1.6 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 55.8 Hz, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H).

m/z: 564.0 [M+H] ⁺ , (ESI+), RT = 2.91 LCMS method 4.

Compound 1534: 3-(4-cyano-2-methoxyphenoxy)-6-[4-(difluoromethyl)phenyl]-N-{3-[(R)-imino(methyl)oxo- λ ⁶ -sulfanyl]phenyl}-5-methylpyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ )) δ 11.29 (s, 1H), 8.40 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.81 - 7.67 (m, 6H), 7.62 (t, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.2, 1.7 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 55.8 Hz, 1H), 4.25 (s, 1H), 3.81 (s, 3H), 3.07 (s, 3H), 2.35 (s, 3H).

m/z: 564.0 [M+H] ⁺ , (ESI+), RT = 2.91 LCMS method 4.

Compound 1535: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(R)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-6-(4- Methoxyphenyl)-5-methylpyridazine-4-carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ 8.46 (t, J = 2.0 Hz, 1H), 7.97 (m, 1H), 7.83 (m, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.46 - 7.38 (m, 2H), 7.12 - 7.06 (m, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.17 (s, 3H), 2.42 ( s, 3H). m/z: 544.1 [M+H] ⁺ , (ESI+), RT = 2.68 LCMS Method 4.

Compound 1536: 3-(4-cyano-2-methoxyphenoxy)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-6-(4- Methoxyphenyl)-5-methylpyridazine-4-carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ 8.46 (t, J = 2.0 Hz, 1H), 7.97 (m, 1H), 7.82 (m, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.53 - 7.46 (m, 3H), 7.45 - 7.36 (m, 2H), 7.13 - 7.04 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.17 (s, 3H), 2.42 ( s, 3H). m/z: 544.4 [M+H] ⁺ , (ESI+), RT = 2.77 LCMS Method 4.

Compound 1537: 3-(4-cyano-2-methoxyphenoxy)-6-(2-fluorophenyl)-N-{3-[(R)-imino(methyl)oxo-λ ⁶ -sul panyl]phenyl}-5-methylpyridazine-4-carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ 8.46 (t, J = 2.0 Hz, 1H), 7.97 (m, 1H), 7.83 (m, J = 7.8, 1.8, 1.0 Hz, 1H), 7.65 (t , J = 8.0 Hz, 1H), 7.59 (m, 1H), 7.52 (d, J = 1.7 Hz, 1H), 7.51 - 7.41 (m, 3H), 7.38 (td, J = 7.5, 1.1 Hz, 1H) , 7.31 (m, 1H), 3.84 (s, 3H), 3.17 (s, 3H), 2.33 (d, J = 1.4 Hz, 3H).

m/z: 532.1 [M+H] ⁺ , (ESI+), RT = 2.71 LCMS Method 4.

Example 79

Compound 1538: 5-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]thiazole-2 -Carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 12.70 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.76 - 7.73 (m, 2H), 7.57 (dd, J = 8.2 , 1.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 3.78 (s, 3H), 2.48 (m, 3H). m/z: 479.1 [M+H] ⁺ , (ESI+), RT = 2.73 MET-uPLC-AB-101 (7 min, low pH).

Compound 1539: N-(6-carbamoyl-3-pyridyl)-3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine- 4-Carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.47 (s, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.32 (dd, J = 8.6, 2.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.08 - 8.01 (m, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.57 (dd, J = 8.2, 1.8 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 3.80 (s, 3H), 2.54 (d, J = 1.4 Hz, 3H).

m/z: 473.1 [M+H] ⁺ , (ESI+), RT = 2.69 MET-uPLC-AB-107 (7 min, high pH)

Compound 1540: 3-(4-cyano-2-methoxy-phenoxy)-N-(5-cyano-3-pyridyl)-5-methyl-6-(trifluoromethyl)pyridazine-4 -Carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ 8.98 (d, J = 2.5 Hz, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.68 (dd, J = 2.5, 1.8 Hz, 1H), 7.54 (d, J = 1.4 Hz, 1H), 7.45 (t, J = 1.3 Hz, 2H), 3.81 (s, 3H), 2.59 (q, J = 1.5 Hz, 3H). m/z: 455.0 [M+H] ⁺ , (ESI+), RT = 3.35 MET-uPLC-AB-101 (7 min, low pH)

Compound 1541: N-(3-carbamoyl-4-methoxy-phenyl)-3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyri Minced-4-carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ 8.14 (d, J = 2.8 Hz, 1H), 8.01 (dd, J = 9.0, 2.8 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.22 (d, J = 9.0 Hz, 1H), 4.00 (s, 3H), 3.81 (s, 3H), 2.61 - 2.55 (m, 3H). m/z: 502.0 [M+H] ⁺ , (ESI+), RT = 3.00 MET-uPLC-AB-101 (7 min, low pH)

Compound 1542: 3-(4-Cyano-2-methoxy-phenoxy)-5-methyl-N-[3-(methylsulfonylcarbamoyl)phenyl]-6-(trifluoromethyl)pyridazine -4-carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ 8.12 (s, 1H), 7.88 - 7.83 (m, 1H), 7.66 - 7.61 (m, 1H), 7.46 - 7.41 (m, 2H), 7.38 - 7.32 ( m, 2H), 3.72 (s, 3H), 3.23 (s, 3H), 2.50 (d, J = 1.4 Hz, 3H). m/z: 550.0 [M+H] ⁺ , (ESI+), RT = 1.97 MET-uPLC-AB-107 (7 min, high pH)

Compound 1543: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-(3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (br.s, 1H), 8.82 (d, J = 2.4 Hz, 1H), 8.39 (dd, J = 4.7, 1.3 Hz, 1H), 8.16 ( ddd, J = 8.3, 2.6, 1.5 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H) ), 7.45 (dd, J = 8.3, 4.7 Hz, 1H), 3.79 (s, 3H), 2.53 - 2.51 (m, 3H). m/z: 430.2 [M+H] ⁺ , (ESI+), RT = 2.99 MET-uPLC-AB-101 (7 min, low pH)

Compound 1544: 3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-(1-oxidopyridin-1-ium-3-yl)-6-(trifluoromethyl) Pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 9.04 (t, J = 1.9 Hz, 1H), 8.21 - 8.15 (m, 1H), 7.76 (m, 1H), 7.60 - 7.52 (m, 2H), 7.45 (s, 2H), 3.81 (s, 3H), 2.58 (m, 3H). m/z: 446.2 [M+H] ⁺ , (ESI+), RT = 2.44 MET-uPLC-AB-101 (7 min, low pH).

Compound 1545: 3-(4-cyano-2-methoxy-phenoxy)-N-[3-[(E)-N-methoxy-C-methyl-carbonimidoyl]phenyl]-5-methyl- 6-(trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 8.03 - 7.98 (m, 1H), 7.78 - 7.71 (m, 2H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H ), 7.50 (d, J = 8.2 Hz, 1H), 7.47 - 7.42 (m, 2H), 3.92 (s, 3H), 3.79 (s, 3H), 2.52 - 2.51 (m, 3H), 2.18 (s, 3H). m/z: 500.0 [M+H] ⁺ , (ESI+), RT = 4.09 MET-uPLC-AB-101 (7 min, low pH).

Compound 1546: Methyl 3-[[3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]benzoate

¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -63.30. m/z: 487.1 [M+H] ⁺ , (ESI+), RT = 3.57 MET-uPLC-AB-107 (7 min, high pH)

Compound 1547: 3-(4-fluoro-2-methyl-phenoxy)-6-(1-hydroxyethyl)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4 -Carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ, 8.46 (t, J = 1.9 Hz, 1H), 8.02 - 7.89 (m, 1H), 7.86 - 7.77 (m, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.16 (dd, J = 8.9, 4.9 Hz, 1H), 7.05 (dd, J = 9.1, 2.9 Hz, 1H), 7.01 - 6.93 (m, 1H), 5.23 (q, J = 6.5 Hz) , 1H), 3.17 (s, 3H), 2.56 (s, 3H), 2.16 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H) The three exchangeable Hs are not visible. m/z: 459.1 [M+H] ⁺ , (ESI+), RT = 2.25 MET-uPLC-AB-107 (7 min, high pH)

Compound 1548: 3-(4-Cyano-2-methoxy-phenoxy)-N-(3-cyanophenyl)-5-methyl-6-(trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.35 (s, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.65 (dt, J = 15.6, 7.7 Hz, 3H), 7.57 (dd, J = 8.2, 1.8 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 3.80 (s, 3H). m/z: 454.2 [M+H] ⁺ , (ESI+), RT = 3.52 MET-uPLC-AB-101 (7 min, low pH).

Compound 1549: N-(3-carbamoylphenyl)-3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-6-(trifluoromethyl)pyridazine-4 -Carboxamide

^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 8.18 (t, J = 1.8 Hz, 1H), 8.01 (br.s, 1H), 7.81 (ddd, J = 8.1, 2.2 , 0.9 Hz, 1H), 7.67 (dt, J = 7.8, 1.0 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.41 (br.s, 1H), 7.33 - 7.26 (m, 1H) , 7.24 (ddd, J = 9.3, 5.2, 1.9 Hz, 1H), 3.83 - 3.79 (m, 3H), 2.54 - 2.52 (m, 3H). m/z: 483.1 [M+H] ⁺ , (ESI+), RT = 3.09 MET-uPLC-AB-101 (7 min, low pH).

Compound 1550: 3-[(6-cyclopropyl-2-methoxy-3-pyridyl)oxy]-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl ) Pyridazine-4-carboxamide

¹ H NMR (500 MHz, CD ₃ OD) δ 8.46 - 8.43 (m, 1H), 7.98 - 7.94 (m, 1H), 7.85 - 7.81 (m, 1H), 7.68 - 7.63 (m, 1H), 7.46 - 7.44 (m, 1H), 6.93 - 6.90 (m, 1H), 3.81 (s, 3H), 3.17 (s, 3H), 2.59 - 2.55 (m, 3H), 2.07 - 2.01 (m, 1H), 1.04 - 0.99 (m, 2H), 0.96 - 0.91 (m, 2H). m/z: 522.3 [M+H] ⁺ , (ESI+), RT = 3.48 MET-uPLC-AB-107 (7 min, high pH).

Compound 1551: 3-(3,4-difluoro-2-methoxy-phenoxy)-5-methyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-6-(tri Fluoromethyl)pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 9.09 (d, J = 7.5 Hz, 1H), 8.67 (s, 1H), 7.48 - 7.39 (m, 1H), 7.18 - 7.01 (m, 2H), 3.86 (s, 3H), 2.61 (s, 3H). m/z: 481.9 [M+H] ⁺ , (ESI+), RT = 3.98 MET-uPLC-AB-101 (7 min, low pH).

Compound 1552: 3-(4-Chloro-3-fluoro-2-methoxy-phenoxy)-5-methyl-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine- 4-carboxamide

^1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 8.38 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.79 - 7.66 (m, 2H), 7.45 (dd, J = 9.0, 7.8 Hz, 1H), 7.28 (dd, J = 9.0, 1.9 Hz, 1H), 3.80 (d, J = 1.2 Hz, 3H), 3.25 (s, 3H), 2.57 - 2.52 (m, 3H). m/z: 534.1, 536.0 [M+H] ⁺ , (ESI+), RT = 3.65 MET-uPLC-AB-101 (7 min, low pH).

Compound 1553: 3-(4-fluoro-2-methyl-phenoxy)-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.19 (s, 1H), 9.06 (s, 1H), 8.38 (t, J = 1.9 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.74 - 7.68 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.28 - 7.16 (m, 2H), 7.10 (td, J = 8.5, 3.1 Hz, 1H), 4.23 (s, 1H), 3.08 - 3.05 (m, 3H), 2.39 (s, 3H), 2.10 (s, 3H) m/z: 414.9 [M+H] ⁺ , (ESI+), RT = 3.19 MET-uPLC-AB-101 (7 minutes) , low pH).

Example 80

3-(4-cyano-2-methoxy-phenoxy)-6-iodo-5-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyryl with appropriate boronate(s) or boronic acid. Compounds 1554, 1555, and 1556 were prepared by a similar procedure described for Example 77 using minced-4-carboxamide coupling.

Compound 1554: 6-(1-Acetyl-3,6-dihydro-2H-pyridin-4-yl)-3-(4-cyano-2-methoxy-phenoxy)-5-methyl-N-[ 3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (t, J = 1.9 Hz, 1H), 7.99 - 7.92 (m, 1H), 7.86 - 7.78 (m, 1H), 7.65 (t, J = 8.0 Hz) , 1H), 7.50 (s, 1H), 7.41 (s, 2H), 6.05 - 5.96 (m, 1H), 4.31 - 4.22 (m, 2H), 3.89 - 3.76 (m, 5H), 3.17 (s, 3H) ), 2.68 - 2.59 (m, 1H), 2.57 - 2.49 (m, 1H), 2.46 (s, 3H), 2.18 ( 2 xs, amide rotomer, 3H).2 Exchangeable H not visible. m/z: 561.1 [M+H] ⁺ , (ESI+), RT = 2.05 MET-uPLC-AB-107 (7 min, high pH)

Compound 1555: 3-(4-Cyano-2-methoxy-phenoxy)-5-methyl-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N-[ 3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (t, J = 1.9 Hz, 1H), 8.00 - 7.90 (m, 1H), 7.85 - 7.77 (m, 1H), 7.65 (t, J = 8.0 Hz) , 1H), 7.50 (s, 1H), 7.41 (s, 2H), 5.95 (dt, J = 2.5, 1.1 Hz, 1H), 3.80 (s, 3H), 3.27 - 3.19 (m, 2H), 3.17 ( s, 3H), 2.77 (t, J = 5.7 Hz, 2H), 2.63 - 2.56 (m, 2H), 2.47 (s, 3H), 2.44 (s, 3H). The two interchangeable H's were not visible. m/z: 533.1 [M+H] ⁺ , (ESI+), RT = 2.20 MET-uPLC-AB-107 (7 min, high pH).

Compound 1556: 3-(4-Cyano-2-methoxy-phenoxy)-6-(2,5-dihydrofuran-3-yl)-5-methyl-N-[3-(methylsulfonimidoyl) )phenyl]pyridazine-4-carboxamide

¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (t, J = 1.9 Hz, 1H), 8.01 - 7.92 (m, 1H), 7.86 - 7.79 (m, 1H), 7.65 (t, J = 8.0 Hz) , 1H), 7.50 (s, 1H), 7.41 (s, 2H), 6.70 - 6.62 (m, 1H), 5.13 (td, J = 4.7, 2.1 Hz, 2H), 4.94 (td, J = 4.7, 1.9 Hz, 2H), 3.80 (s, 3H), 3.17 (s, 3H), 2.60 (s, 3H) 2 interchangeable H not visible. m/z: 506.1 [M+H] ⁺ , (ESI+), RT = 2.24 MET-uPLC-AB-107 (7 min, high pH).

Example 81

Exemplary compounds of the invention are provided below. The number of each compound is provided immediately below its structural formula.

Table 14

Example 82

General synthetic route for synthesis of substituted analogues

Compound 1557:

Route 1: 2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide

Reagents & Conditions: a) 4-fluoro-2-methylphenol, NaH, DMF; b) Methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, CuI, HMPA, DMF, 160°C; c) KOH, MeOH/H ₂ O, 160°C; d) tert-butyl ((3-aminophenyl) (methyl)(oxo)-λ6-sulfanylidene)carbamate, POCl ₃ , pyr, 0° C.; e) TFA, DCM

Step 1: Methyl 5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate: 4-fluoro-2-methylphenol (1.08 g, 8.5 g) in DMF (7 mL) Sodium hydride (60%, 0.21 g, 8.5 mmol) was added to the solution of (mmol). The mixture was stirred at room temperature for 0.5 hours. The mixture was then added to a solution of methyl 5-bromo-2-chloro-4-methylpyridine-3-carboxylate (1.5 g, 5.7 mmol) in DMF (8 mL). The mixture was heated at 70° C. for 4 hours. LCMS showed the reaction was complete. The resulting solution was quenched with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 2/1) to give methyl 5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate. (1.1 g, 49.2% yield) was obtained. LC-MS: (ESI) C ₁₅ H ₁₄ BrFNO ₃ [M + H] ⁺ calcd for m/z 356.02, found 355.90.

Step 2: Methyl 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl) nicotinate: Methyl 5-bromo-2-( in NMP (10 mL) 4-fluoro-2-methylphenoxy)-4-methylpyridine-3-carboxylate (500 mg, 1.41 mmol), HMPA (506 mg, 2.82 mmol) and copper (I) iodide (538 mg, To the stirred solution (2.82 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (1.36 g, 7.06 mmol) was added dropwise at 150°C in an N ₂ atmosphere. The mixture was heated at 150°C for 2 hours. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 2/1) to give methyl 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl ) Nicotinate (260 mg, 37.6% yield) was obtained. LC-MS: (ESI) C ₁₆ H ₁₄ F ₄ NO ₃ [M + H] ⁺ calcd for m/z 344.09, found 344.00.

Step 3: 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid: Methyl 2-( in MeOH/H ₂ O (1/1, 4 mL) To a solution of 4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinate (250 mg, 0.73 mmol) was added KOH (384 mg, 5.83 mmol) at room temperature. . The mixture was heated at 70° C. for 4 hours. After the reaction was complete, the mixture was concentrated to remove most of the MeOH. The aqueous phase was adjusted to pH = 3-4 using 1N HCl and then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid ( 210 mg, 78.8% yield) was obtained as a white solid. LC-MS: (ESI) calculated. C ₁₅ H ₁₂ F ₄ NO ₃ [M + H] ⁺ m/z 330.08, actual value 329.95.

Step 4: tert-Butyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo) -λ ⁶ -sulfanylidene)carbamate: 2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinic acid (240 mg, in pyridine (5 mL)) 0.73 mmol) and tert-butyl ((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (295 mg, 1.09 mmol) in POCl ₃ (200 μL) at 0°C. It was added dropwise. The reaction solution was stirred at 0°C for 1 hour. After the reaction was complete, the resulting solution was quenched with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 2/1) to give tert-butyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-methyl- 5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (70 mg, 14.9% yield) was obtained as a white solid. LC-MS: (ESI) C ₂₇ H ₂₈ F ₄ N ₃ O ₅ S [M + H] ⁺ calcd for m/z 582.17, found 582.15.

Step 5: 2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide: DCM (1.5 mL) of tert-butyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)( To a solution of oxo)-λ6-sulfanylidene)carbamate (70 mg, 0.12 mmol) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated. The residue was dissolved in THF (2 mL) and then adjusted to pH = 8-9 using saturated aqueous NaHCO ₃ . The resulting solution was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini 5 um C ₁₈ column, 150*21.2 mm, eluting with 40% to 85% MeCN/H ₂ O (containing 0.1% FA)) to give 2-(4-fluoro -2-Methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (32.1 mg, 52%) was obtained as a white solid. did. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 11.17 (s, 1 H), 8.52 (s, 1 H), 8.41 (s, 1 H), 7.89 (d, J = 8.0 Hz, 1 H ), 7.70 (d, J = 7.8 Hz, 1 H), 7.61 (t, J = 7.9 Hz, 1 H), 7.19 (dd, J = 8.6, 5.2 Hz, 2 H), 7.09 (td, J = 8.5 , 2.9 Hz, 1 H), 4.24 (s, 1 H), 3.07 (s, 3 H), 2.48 (s, 3 H), 2.08 (s, 3 H). LC-MS: (ESI) C ₂₂ H ₂₀ F ₄ N ₃ O ₃ S [M + H] ⁺ calcd for m/z 482.12, found 482.00.

Route 2: 2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide

Reagents & Conditions: a) K ₂ CO ₃ , acetonitrile, 60°C; b) Methyl difluoro(fluorosulfonyl)acetate, CuI, TBAI, DMF, 70°C; c) Barium hydroxide, H ₂ O, 90° C., 70 hours; d) 1-Bromo-3-(methylsulfanyl)benzene, Pd ₂ (dba) ₃ , XantPhos, 1,4-dioxane, 100°C; Bis(acetoxy)iodobenzene, (NH ₄ )CO ₃ , MeOH.

Step 1: 2-(4-Fluoro-2-methyl-phenoxy)-5-iodo-4-methyl-pyridine-3-carbonitrile: 4-fluoro-2-methyl in acetonitrile (5 mL) -mixture of phenol (533 mg, 4.22 mmol), 2-chloro-5-iodo-4-methyl-pyridine-3-carbonitrile (980 mg, 3.52 mmol) and K ₂ CO ₃ (584 mg, 4.22 mmol) was stirred at 60°C for 16 hours. The reaction mixture was retreated with 4-fluoro-2-methyl-phenol (533 mg, 4.22 mmol) and stirred at 60° C. for an additional 6 hours. The reaction was cooled to room temperature, filtered, and washed with MeCN (20 mL). The filtrate was concentrated under vacuum to give a crude residue. Purification by chromatography on silica (Biotage Isolera, 50 g Spa Duo column) eluting with a gradient of 0 to 13% EtOAc in heptane gave 2-(4-fluoro-2-methyl-phenoxy)-5. -Iodo-4-methyl-pyridine-3-carbonitrile (94.0%) (930 mg, 2.37 mmol, 67%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 7.25 - 7.18 (m, 2H), 7.14 - 7.05 (m, 1H), 2.62 (s, 3H), 2.08 (s, 3H) ). m/z: 369.1 [M+H] ⁺ , (ESI+), RT = 1.04 LCMS Method 2

Step 2: 2-(4-Fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carbonitrile: 2-(4-fluoro in DMF (10 mL) Ro-2-methyl-phenoxy)-5-iodo-4-methyl-pyridine-3-carbonitrile (94%, 930 mg, 2.37 mmol), iodoguri (682 mg, 3.56 mmol), and tetrabutyl To a mixture of ammonium;iodide (352 mg, 0.950 mmol), methyl difluoro(fluorosulfonyl)acetate (2281 mg, 11.9 mmol) was added and stirred at 70°C for 16 hours. The reaction was cooled to room temperature, filtered, and washed with EtOAc (2 x 10 mL). The filtrate was washed with brine (20 mL), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a crude residue. Purification by chromatography on silica (Biotage Isolera, 50 g Spa Duo column) eluting with a gradient of 0 to 5% EtOAc in heptane gave 2-(4-fluoro-2-methyl-phenoxy)-4. -Methyl-5-(trifluoromethyl)pyridine-3-carbonitrile (533 mg, 1.39 mmol, 59% yield) was obtained as a yellow solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 7.29 - 7.22 (m, 2H), 7.13 (td, J = 8.5, 3.2 Hz, 1H), 2.70 - 2.66 (m, 3H) ), 2.10 (s, 3H). m/z: 311.3 [M+H] ⁺ , (ESI+), RT = 1.02 LCMS method 2

Step 3: 2-(4-Fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carboxamide: 2-(4-fluoro-2-methyl -Phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carbonitrile (533 mg, 1.39 mmol) was suspended in water (4 mL) and barium hydroxide (1.19 g, 6.96 mmol) was added. Added. The resulting mixture was stirred at 90°C for 16 hours. The reaction mixture was diluted with water (4 mL) and retreated with barium hydroxide (1.19 g, 6.96 mmol). Stirring at 90° C. was resumed for a total of 70 hours. The cooled reaction mixture was diluted with water (50 mL) and acidified to pH 1 with 5M HCl. The aqueous layer was extracted with EtOAc (3 x 15 mL) and the combined organics were dried over MgSO ₄ and concentrated under reduced pressure. The crude product was purified by FCC (Biotage Isolera 4, 10 g Spa Duo, Lambda-all collection) using a gradient of 0-50-100% EtOAc/heptane followed by 0-20% MeOH/EtOAc. Product fractions were combined and concentrated under reduced pressure to give 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carboxamide (98.0%) (220 mg, 47%) was obtained as a white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (s, 1H), 8.16 (br.s, 1H), 7.90 (br.s, 1H), 7.21 - 7.04 (m, 3H), 2.42 (s) , 3H), 2.07 (s, 3H). m/z: 329.1 [M+H] ⁺ , (ESI+), RT = 0.81 LCMS method 2.

Step 4: 2-(4-Fluoro-2-methyl-phenoxy)-4-methyl-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: 2-(4-Fluoro-2-methyl-phenoxy)-4-methyl-5-(trifluoromethyl)pyridine-3-carboxamide (98) in 1,4-dioxane-anhydrous (3 mL) %, 200 mg, 0.597 mmol), (1E,4E)- 1,5-diphenylpenta-1,4-dien-3-one - palladium (3:2) Pd ₂ (dba) ₃ (27 mg, 0.0295 mmol) and (9,9-dimethyl-9H-xanthene- 4,5-diyl)bis(diphenylphosphane [XantPhos] (35 mg, 0.0605 mmol) was added. The reaction was degassed for an additional 5 minutes, then the vial was sealed and stirred at 100°C for 4 hours. The cooled reaction mixture was diluted with EtOAc (5 mL) and filtered through a pad of Celite. The Celite was washed with EtOAc (2 x 3 mL) and the combined filtrates were washed with saturated aqueous sodium bicarbonate solution (10 mL). ) followed by washing with brine (10 mL).The organic phase was dried using a phase separation cartridge and concentrated under vacuum to give 352 mg as a yellow solid.The crude product was purified by column chromatography (Spa Duo 10 g, heptane Purified by lambda-all collections, eluting with 0-100% EtOAc. Product fractions were combined and concentrated under reduced pressure to give the desired product, 2-(4-fluoro-2-methyl-phenoxy)-4- Methyl-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (72.0%) (240 mg, 0.384 mmol, 64%) was obtained as a light yellow powder. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 8.50 (s, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.31 ( t, J = 8.0 Hz, 1H), 7.21 - 7.16 (m, 2H), 7.09 (td, J = 8.5, 2.9 Hz, 1H), 7.04 (ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 2.48 - 2.44 (m, 6H), 2.08 (s, 3H). m/z: 451.1 [M+H] ⁺ , (ESI+), RT = 1.09 LCMS Method 2.

Step 5: 2-(4-Fluoro-2-methyl-phenoxy)-4-methyl-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-car Boxamide: 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine- in methanol (7.5 mL) To a solution of 3-carboxamide (72%, 240 mg, 0.384 mmol), bis(acetoxy)iodobenzene (395 mg, 1.23 mmol) and ammonium carbonate (75 mg, 0.797 mmol) were added and the reactants were It was stirred at room temperature for 15 hours. The reaction mixture was retreated with bis(acetoxy)iodobenzene (132 mg, 0.410 mmol) and ammonium carbonate (25 mg, 0.266 mmol), stirred for 2 hours and then left at ambient temperature over the weekend. Stirring was resumed for 1 hour and then worked up. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography using 0-100% EtOAc in heptane followed by 0-20% MeOH in EtOAc (on a Biotage Spa Duo 10 g column, Lambda -all collections). The resulting residue was dried in a vacuum oven at 40°C for 2 hours to obtain 2-(4-fluoro-2-methyl-phenoxy)-4-methyl-N-[3-(methylsulfonimidoyl)phenyl]- 5-(Trifluoromethyl)pyridine-3-carboxamide (95.0%) (98 mg, 0.193 mmol, 50%) was obtained as an off-white powder. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.17 (s, 1H), 8.51 (s, 1H), 8.44 - 8.37 (m, 1H), 7.92 - 7.84 (m, 1H), 7.72 - 7.67 (m , 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.09 (td, J = 8.5, 3.0 Hz, 1H), 4.23 (s, 1H), 3.07 (s, 3H), 2.49 - 2.47 (m, 3H), 2.08 (s, 3H). m/z: 482.2 [M+H] ⁺ , (ESI+), RT = 3.12 LCMS Method 4.

Example 83

Compound 1558: 5-Chloro-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide

Reagents & Conditions: a) NCS, DCM, 0°C; b) PhOPOCl ₂ , 170°C; c) 4-fluoro-2-methylphenol, NaH, DMF, 70°C; d) KOH, MeOH/H ₂ O, 60°C; e) tert-butyl ((3-aminophenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate, SOCl ₂ , 50° C.; followed by DIPEA, DCM, 0°C; f) TFA, DCM

Step 1: Methyl 5-chloro-2-hydroxy-4-methylnicotinate: Methyl 4-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (5.0) in DCM (50 mL) g, 30 mmol), NCS (4.0 g, 30 mmol) was added at 0°C. The mixture was stirred at the same temperature for 60 minutes. The mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by trituration (PE/EtOAc = 3/1) to give methyl 5-chloro-2-hydroxy-4-methylnicotinate (4 g, 66% yield) as a light brown solid. LC-MS: (ESI) Calculated for C ₈ H ₉ ClNO ₃ [M + H] ⁺ m/z 202.02, found 202.0.

Step 2: Methyl 2,5-dichloro-4-methylnicotinate: Solution of methyl 5-chloro-2-hydroxy-4-methylnicotinate (2.0 g, 10 mmol) in phenyl dichlorophosphate (10 mL) was heated to 170°C for 2 hours. The resulting solution was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 10/1) to give methyl 2,5-dichloro-4-methylnicotinate (1 g, 45% yield) as a pale yellow oil. . LC-MS: (ESI) C ₈ H ₈ Cl ₂ NO ₂ [M + H] ⁺ calcd for m/z 219.99, found 220.0.

Step 3: Methyl 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate: 4-fluoro-2-methylphenol (286 mg, 2.27 mg) in DMF (5 mL) mmol) was added NaH (60%, 110 mg, 2.72 mmol) at 0°C. The mixture was stirred at the same temperature for 60 minutes, then 2,5-dichloro-4-methylnicotinate (500 mg, 2.27 mmol) was added. The mixture was heated at 70° C. for 16 hours. The resulting mixture was quenched with water (20 mL) and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc = 3/1) to give methyl 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinate (250 mg, 35% yield) was obtained as a light yellow oil. ¹ H NMR (400 MHz, CDCl ₃ , ppm) δ 8.05 (s, 1 H), 7.06 - 6.76 (m, 3 H), 3.98 (s, 3 H), 2.39 (s, 3 H), 2.13 (s , 3 H).

Step 4: 5-Chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinic acid: Methyl 5-chloro-2-(4-fluoro-2-methylphenocyl) in MeOH (5 mL) To a solution of si)-4-methylnicotinate (250 mg, 0.81 mmol) was added a solution of KOH (453 mg, 8.1 mmol) in water (2 mL). The solution was heated at 60°C for 16 hours. The resulting mixture was adjusted to pH=3-4 using 1N HCl and extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo to give 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinic acid (150 mg, 63% yield). Obtained as a white solid. LC-MS: (ESI) C ₁₄ H ₁₂ ClFNO ₃ [M + H] ⁺ calcd for m/z 296.04, found 296.0.

Step 5: tert-Butyl ((3-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfa Nylidene)carbamate: A solution of 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinic acid (100 mg, 0.34 mmol) in SOCl ₂ (1 mL) was brought to 50°C. Heated and stirred for 0.5 hours. The solution was concentrated under vacuum to give the chloride intermediate. The chloride intermediate was then incubated with tert-butyl ((3-aminophenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate (92 mg, 0.34 mmol) and DIPEA in DCM (2 mL) at 0°C. (88 mg, 0.68 mmol) was added to the stirred solution. The resulting mixture was stirred at 25°C for 1 hour. The mixture was then quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give tert-butyl ((3-(5-chloro-2-(4-fluoro-2-methylphenoxy)- 4-Methylnicotinamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (80 mg, 43% yield) was obtained as a white oil. LC-MS: (ESI) C ₂₆ H ₂₈ ClFN ₃ O ₅ S [M + H] ⁺ calcd for m/z 548.13, found 548.0.

Step 6: Preparation of 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide: DCM (5 mL ) of tert-butyl ((3-(5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methylnicotinamido) phenyl) (methyl)(oxo)-sulfanylidene) car To a solution of bamate (80 mg, 0.14 mmol) was added TFA (1 mL) at 0°C. The mixture was stirred at 25°C for 1 hour. The resulting mixture was adjusted to pH = 8-9 using saturated aqueous NaHCO3 and extracted with DCM (10 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated in vacuo and the residue was purified by preparative HPLC (Gemini 5 um C ₁₈ column, 150*21.2 mm, 30% to 90% MeCN/H ₂ O (0.1 5-chloro-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl) Nicotinamide (25 mg, 38%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 11.09 (s, 1 H), 8.41 (s, 1 H), 8.22 (s, 1 H), 7.88 (d, J = 8.1 Hz, 1 H ), 7.69 (d, J = 7.9 Hz, 1 H), 7.60 (t, J = 7.9 Hz, 1 H), 7.16 (dd, J = 8.8, 4.6 Hz, 2 H), 7.10 -7.03 (m, 1 H), 4.23 (s, 1 H), 3.06 (s, 3 H), 2.39 (s, 3 H), 2.08 (s, 3 H). LC-MS: (ESI) C ₂₁ H ₂₀ ClFN ₃ O ₃ S [M + H] ⁺ calcd for m/z 448.08, found 448.05.

Example 84

Compound 1559: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (Trifluoromethyl)nicotinamide

Reagents & Conditions: a) H ₂ O ₂ , NaOH, THF/H ₂ O; b) Methyl 5-bromo-2-chloro-4-methylnicotinate, NaH, DMF, 70°C; c) Methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, CuI, HMPA, DMF, 160°C; d) KOH, MeOH/H ₂ O, 70°C; e) (R)-tert-butyl ((3-aminophenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate, SOCl ₂ , DIPEA, DCM; f) TFA, DCM

Step 1: 6-Fluoro-2-methylpyridin-3-ol: To a solution of (6-fluoro-2-methylpyridin-3-yl)boronic acid (2.5 g, 16.12 mmol) in THF (20 mL) NaOH (516 mg, 12.89 mmol), H ₂ O (5 mL) and H ₂ O ₂ (1 mL, 30%) were added at 0°C. The mixture was stirred at room temperature for 1 hour. The mixture was then adjusted to pH = 3-4 using 1N HCl and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 3/1) to give 6-fluoro-2-methylpyridin-3-ol (1.8 g, 70.59% yield) as a yellow solid. . LCMS: (ESI) C ₆ H ₆ FNO [M + H] ⁺ calculated for m/z 128.05, found 128.15.

Step 2: Methyl 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate: 6-fluoro-2- in DMF (8 mL) To a solution of methylpyridin-3-ol (1.50 g, 11.81 mmol) was added sodium hydride (60%, 977 mg, 23.62 mmol) at 0°C. The mixture was stirred at room temperature for 0.5 hours. The mixture was then added to a stirred solution of methyl 5-bromo-2-chloro-4-methylnicotinate (2.08 g, 7.91 mmol) in DMF (8 mL). The mixture was heated at 70° C. for 4 hours. LCMS showed the reaction was complete. The resulting solution was quenched with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 2/1) to give methyl 5-bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)- 4-Methylnicotinate (0.71 g, 16.9% yield) was obtained. LC-MS: (ESI) C ₁₄ H ₁₃ BrFN ₂ O ₃ [M + H] ⁺ calcd for m/z 355.01, found 354.95.

Step 3: Methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinate: Methyl 5- in NMP (10 mL) Bromo-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methylnicotinate (650 mg, 1.84 mmol), HMPA (658 mg, 3.68 mmol) and iodination To a stirred solution of copper (I) (703 mg, 3.68 mmol) was added dropwise methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (3.53 g, 18.4 mmol) at 150°C under an atmosphere of N ₂ did. The mixture was heated at 150°C for 2 hours. After the reaction was completed, the resulting solution was diluted with water (60 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 2/1) to give methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5 -(Trifluoromethyl)nicotinate (330 mg, 51.9% yield) was obtained. LC-MS: (ESI) C ₁₅ H ₁₃ F ₄ N ₂ O ₃ [M + H] ⁺ calcd for m/z 345.09, found 345.05.

Step 4: 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinic acid: THF/H ₂ O (1/1, 4 mL ) in a solution of methyl 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinate (300 mg, 0.87 mmol) at room temperature. KOH (487 mg, 8.69 mmol) was added. The mixture was heated at 70° C. for 4 hours. After the reaction was complete, the mixture was concentrated to remove most of the THF. The aqueous phase was adjusted to pH = 3-4 using 1N HCl and then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(tri Fluoromethyl)nicotinic acid (280 mg, 97.2%) was obtained as a white solid. LC-MS: (ESI) C ₁₄ H ₁₁ F ₄ N ₂ O ₃ [M + H] ⁺ calcd for m/z 331.07, found 331.00.

Step 5: tert-Butyl (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinami do) phenyl) (methyl) (oxo) -λ ⁶ -sulfanylidene) carbamate: 2-((6-fluoro-2-methylpyridin-3-yl)oxy)- in SOCl ₂ (1 mL) A solution of 4-methyl-5-(trifluoromethyl)nicotinic acid (120 mg, 0.36 mmol) was heated to 50° C. and stirred for 0.5 h. The solution was concentrated under vacuum to give the chloride intermediate. The chloride intermediate was then purified with tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (117 mg, 0.43 mg) in DCM (2 mL) at 0°C. mmol) and DIEA (88 mg, 0.68 mmol). The resulting mixture was stirred at 25°C for 1 hour. The mixture was then quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give tert-butyl (R)-((3-(2-((6-fluoro-2-methylpyridine-3 -yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfanylidene)carbamate (100 mg, 47.6%) as white oil It was obtained as. LC-MS: (ESI) C ₂₆ H ₂₇ F ₄ N ₄ O ₅ S [M + H] ⁺ calcd for m/z 583.17, found 583.10.

Step 6: (R)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (Trifluoromethyl)nicotinamide: tert-butyl (R)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- in DCM (1.5 mL) TFA (0.5 mL) was added to a solution of methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ6-sulfanylidene)carbamate (100 mg, 0.17 mmol) at room temperature. Added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated. The residue was dissolved in THF (2 mL) and then adjusted to pH = 8-9 using saturated aqueous NaHCO ₃ . The resulting solution was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini 5 um C ₁₈ column, 150*21.2 mm, eluting with 40% to 95% MeCN/H ₂ O containing 0.05% NH ₄ OH) to give (R)-2. -((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (57.2 mg, 69.6%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 11.20 (s, 1 H), 8.55 (s, 1 H), 8.41 (s, 1 H), 7.96-7.78 (m, 2 H), 7.74 -7.56 (m, 2 H), 7.11 (dd, J = 8.7, 3.4 Hz, 1 H), 4.24 (s, 1 H), 3.32 (s, 3 H), 3.07 (s, 3 H), 2.25 ( s, 3 H). LC-MS: (ESI) C ₂₁ H ₁₉ F ₄ N ₄ O ₃ S [M + H] ⁺ calcd for m/z 483.11, found 483.00.

Example 85

Compound 1560: (S)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (Trifluoromethyl)nicotinamide

Reagents & Conditions: a) (S)-tert-Butyl ((3-aminophenyl) (methyl)(oxo)- -λ ⁶ -sulfanylidene)carbamate, SOCl ₂ , DIPEA, DCM; b) TFA, DCM

Step 1: tert-Butyl (S)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinami do) phenyl) (methyl) (oxo) -λ ⁶ -sulfanylidene) carbamate: 22-((6-fluoro-2-methylpyridin-3-yl)oxy)- in SOCl ₂ (1 mL) A solution of 4-methyl-5-(trifluoromethyl)nicotinic acid (120 mg, 0.36 mmol) was heated to 50° C. and stirred for 0.5 h. The solution was then concentrated under vacuum to obtain the chloride intermediate. The chloride intermediate was then purified with tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (117 mg, 0.43 mg) in DCM (2 mL) at 0°C. mmol) and DIEA (88 mg, 0.68 mmol). The resulting mixture was stirred at 25°C for 1 hour. The mixture was then quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE/EtOAc = 1/1) to give tert-butyl (S)-((3-(2-((6-fluoro-2-methylpyridine-3 -yl)oxy)-4-methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (100 mg, 47.6% yield) Obtained as a white oil. LC-MS: (ESI) C ₂₆ H ₂₇ F ₄ N ₄ O ₅ S [M + H] ⁺ calcd for m/z 583.17, found 583.15.

Step 2: (S)-2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (Trifluoromethyl)nicotinamide: tert-butyl (S)-((3-(2-((6-fluoro-2-methylpyridin-3-yl)oxy)-4- in DCM (1.5 mL) A solution of methyl-5-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (100 mg, 0.17 mmol) in TFA (0.5 mL) at room temperature. was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated. The residue was dissolved in THF (2 mL) and then adjusted to pH = 8-9 using saturated aqueous NaHCO ₃ . The resulting solution was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini 5 um C ₁₈ column, 150*21.2 mm, eluting with 40% to 95% MeCN/H ₂ O containing 0.05% NH ₄ OH) to give (S)-2. -((6-fluoro-2-methylpyridin-3-yl)oxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (61.3 mg, 74.6% yield) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 11.20 (s, 1 H), 8.55 (s, 1 H), 8.41 (s, 1 H), 7.99-7.76 (m, 2 H), 7.76 -7.52 (m, 2 H), 7.11 (dd, J = 8.6, 3.4 Hz, 1 H), 4.24 (s, 1 H), 3.32 (s, 3 H), 3.07 (s, 3 H), 2.25 ( s, 3 H). LC-MS: (ESI) C ₂₁ H ₁₉ F ₄ N ₄ O ₃ S [M + H] ⁺ calcd for m/z 483.11, found 482.95.

Example 86

Exemplary compounds of the invention are provided below.

Compound 1561: General Route 1: 2-(4-cyano-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

Reagents & Conditions: a) K ₂ CO ₃ , ACN, 70°C; b) LiOH, THF, water, room temperature; c) EDC, 3-aminobenzenesulfonamide, pyridine

Step 1: Methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate: 2-chloro- in acetonitrile-anhydrous (2.5 mL) A mixture of 5-trifluoromethyl-nicotinic acid methyl ester (100 mg, 0.417 mmol), 4-hydroxy-3-methoxybenzonitrile (93 mg, 0.624 mmol) and potassium carbonate (87 mg, 0.629 mmol) was reduced under reduced pressure. The vial was stirred at 70°C for 18 hours. The reaction mixture was allowed to cool to room temperature, diluted with MeCN, filtered through a phase separator and the solid was washed with MeCN (2×). The combined filtrates were concentrated under reduced pressure to give the crude material. This crude compound was purified by FCC (Biotage Isolera 4 flash purification system, Spa Duo 10 g, 0-40% EtOAc in heptane) to give the desired product, methyl 2-(4-cyano-2-methoxy- Phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (94.0%) (142 mg, 0.379 mmol, 91%) was obtained as a white powder. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.73-8.70 (m, 1H), 8.60 -8.58 (m, 1H), 7.69 -7.66 (m, 1H), 7.54 - 7.50 (m, 1H), 7.44 - 7.41 (m, 1H), 3.90 (s, 3H), 3.74 (s, 3H). LC-MS method 2. m/z 353.1 [M+H] ⁺ , (ESI+), RT = 0.96.

Step 2. 2-(4-Cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid: Methyl 2 in THF (2 mL) and water (0.5 mL) In a mixture of -(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (142 mg, 0.403 mmol), lithium hydroxide monohydrate (35 mg, 0.834 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and adjusted to pH 2 by dropwise addition of 2M HCl. Extracted with EtOAc (3×), dried over MgSO ₄ and concentrated in vacuo to give the desired product, 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3. -Carboxylic acid (94.0%) (127 mg, 0.353 mmol, 88% yield) was obtained as a white powder. The product was used in the next step crude material.

Step 3. 2-(4-Cyano-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: Pyridine (1.2 mL ) of 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (94%, 63 mg, 0.175 mmol) and N-[3- To a solution of (dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (1:1) (67 mg, 0.350 mmol) was added 3-aminobenzenesulfonamide (60 mg, 0.348 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed (co-evaporated with MeCN) and the residue was purified by preparative HPLC (purification method 3). Fractions containing the desired product were combined and evaporated to give a white powder, which was freeze-dried overnight to give the desired product, 2-(4-cyano-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl )-5-(Trifluoromethyl)pyridine-3-carboxamide (98.0%) (53 mg, 0.105 mmol, 60% yield) was obtained as an off-white powder. ^1H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.68 - 8.64 (m, 1H), 8.57 - 8.54 (m, 1H), 8.32 - 8.29 (m, 1H), 7.87 - 7.83 ( m, 1H), 7.70 - 7.68 (m, 1H), 7.61 - 7.49 (m, 4H), 7.44 - 7.38 (m, 2H), 3.76 (s, 3H). LC-MS method 4: m/z 493.1 [M+H] ⁺ , (ESI+), RT = 3.24.

Compound 1562: 2-(4-cyano-2-methoxyphenoxy)-N-{3-[imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-(trifluoromethyl)pyridine -3-carboxamide

Reagents & Conditions: a) HATU, DIPEA, DMF, 3-(methylthio)aniline; b) (NH ₄ ) ₂ CO ₃ , PIDA, MeOH

Step 1: 2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: DMF (1.2 mL) of 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (71 mg, 0.210 mmol), DIPEA (0.11 mL, 0.630 mmol) ) and HATU (96 mg, 0.252 mmol) were added to 3-(methylthio)aniline (31 uL, 0.252 mmol). The reaction was stirred at room temperature for 4 hours. The reaction mixture was then poured into water and extracted with EtOAc (2×). The combined organic phases were washed with aqueous brine (2×), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by FCC (Biotage Isolera 4, 10 g Spa Duo, Lambda-all collection) using a 0-50% EtOAc/heptane gradient to give 2-(4-cyano-2-methoxy -Phenoxy)-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (80.0%) (68 mg, 0.118 mmol, 56% yield) as a brown oil. Obtained. ^1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.66 - 8.64 (m, 1H), 8.54 - 8.51 (m, 1H), 7.72 - 7.66 (m, 2H), 7.57 - 7.49 ( m, 2H), 7.48 - 7.43 (m, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.05 - 7.01 (m, 1H), 3.76 (s, 3H), 2.48 - 2.47 (m, 3H) . LC-MS method 2: m/z 460.1 [M+H] ⁺ , (ESI+), RT = 1.06.

Step 2: 2-(4-Cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide: Diammonium carbonate (20 mg, 0.213 mmol) and bis(acetyloxy)(phenyl)-lambda~3~iodane (PIDA) (107 mg, 0.332 mmol) were lysed with 2-(4-cyanyl) in methanol (0.8 mL). In a solution of no-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (96%, 68 mg, 0.142 mmol) Added at room temperature and the reaction was stirred at room temperature for 17 hours. The reaction mixture was concentrated to dryness under vacuum to give the crude product, which was then purified using FCC (0-100% EtOAc, 10 g Spa Duo, dry loading on silica using DCM). Fractions 9-12 were combined, evaporated, and freeze-dried overnight to give the desired product, 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5- (Trifluoromethyl)pyridine-3-carboxamide (99.0%) (49 mg, 0.0989 mmol, 70% yield) was obtained as an off-white powder. ^1H NMR (500 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.68 - 8.65 (m, 1H), 8.56 (d, 1H), 8.39 - 8.35 (m, 1H), 7.97 - 7.92 (m, 1H), 7.72 - 7.67 (m, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.56 - 7.48 (m, 2H), 4.23 (s, 1H), 3.76 (s, 3H), 3.06 (s) , 3H). LC-MS method 4: m/z 491.1 [M+H] ⁺ , (ESI+), RT = 2.94.

Compound 1563: General Route 2: 2-[4-(difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

Reagents & Conditions: a) 50% propylphosphonic anhydride, DIPEA, DMAP, 3-(methylsulfonyl)aniline; b) 4-(difluoromethoxy)phenol, K ₂ CO ₃ , ACN, 60°C

Step 1. 2-Chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: 2-Chloro-5-(trifluoromethyl)pyridine- in EtOAc 3-Carboxylic acid (2.00 g, 8.87 mmol), 50% propylphosphonic anhydride solution (50%, 6.3 mL, 10.6 mmol), N-ethyl-N-isopropyl-propan-2-amine (3.1 mL, 17.7 mL) mmol) and N,N-dimethylpyridin-4-amine (0.22 g, 1.77 mmol) was dissolved in DCM (44.336 mL) at room temperature under nitrogen. After 10 minutes, 3-(methylsulfonyl)aniline (1.82 g, 10.6 mmol) was added in 1 portion. The reaction mixture was stirred at room temperature for 4 hours. IPC indicated the desired product. The reaction mixture was poured into water (20 mL) and brine (10 mL), extracted with DCM (3 x 50 mL), dried over sodium sulfate and concentrated. Purified by chromatography on silica eluting with a gradient of 0 to 38% EtOAc in heptane to give 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide. (99.0%) (1.90 g, 4.97 mmol, 56% yield) was obtained as a yellow solid. ^1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.05 - 9.00 (m, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.34 (t, J = 1.8 Hz, 1H) ), 7.97 - 7.92 (m, 1H), 7.76 - 7.66 (m, 2H), 3.24 (s, 3H). LC-MS method 1: m/z 378.95 [M+H] ⁺ , (ESI+), RT = 1.09.

Step 2: 2-[4-(difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: Acetonitrile (0.5411 mL ) of 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (99%, 100 mg, 0.261 mmol), 4-(difluoromethoxy ) A mixture of phenol (63 mg, 0.392 mmol) and dipotassium carbonate (54 mg, 0.392 mmol) was stirred at 60°C for 1 hour. IPC1 represented the desired product. The reaction was cooled to room temperature, filtered, and washed with MeCN (15 mL). The filtrate was concentrated under vacuum to give a crude residue. Purified by chromatography on silica, eluting with a gradient of 0 to 70% EtOAc in heptane, 2-[4-(difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl)-5-(tri Fluoromethyl)pyridine-3-carboxamide (99.0%) (102 mg, 0.200 mmol, 77% yield) was obtained as an off-white solid. ^1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.71 - 8.66 (m, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.38 (t, J = 1.8 Hz, 1H) ), 7.97 (dt, J = 7.6, 1.7 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.41 - 7.08 (m, 5H), 3.22 (s, 3H). LC-MS method 5: m/z 502.9 [M+H] ⁺ , (ESI+), RT = 4.44.

Compound 1564: General Route 3: N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)-2-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxyx amides

Reagents & Conditions: a) 50% propylphosphonic anhydride, DIPEA, DMAP, 3-(methylsulfonyl)aniline; b) (NH ₄ ) ₂ CO ₃ , PIDA, MeOH; c) 4-(trifluoromethyl)phenol, K ₂ CO ₃ , 60°C

Step 1: 2-Chloro-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide: 2-chloro- dissolved in DCM (80 mL) under air at room temperature. A mixture of 5-(trifluoromethyl)pyridine-3-carboxylic acid (4.00 g, 17.7 mmol) was dissolved in 50% propylphosphonic anhydride solution in EtOAc (50%, 13 mL, 21.3 mmol), and N-ethyl- Treated with N-isopropyl-propan-2-amine (6.2 mL, 35.5 mmol). Then, it was stirred at room temperature for 30 minutes. Then N,N-dimethylpyridin-4-amine (0.43 g, 3.55 mmol) and 3-(methylsulfanyl)aniline (2.2 mL, 17.7 mmol) were added together in 1 part. The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water (60 mL) and brine (60 mL), extracted with DCM (3 x 40 mL), dried (MgSO ₄ ) and concentrated. Purification by column chromatography (50 g, 0 to 10% EA in heptane) gave 2-chloro-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (6.12 g, 17.6 mmol, 100% yield) was obtained as a yellow solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.04 - 8.98 (m, 1H), 8.66 (d, J = 2.1 Hz, 1H), 7.66 (s, 1H), 7.34 (t , J = 7.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 2.49 (s, 3H). LC-MS method 1: m/z 347.1 [M+H] ⁺ , (ESI+), RT = 0.93.

Step 2: 2-Chloro-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide: [acetoxy(phenyl)-$l^{3} -iodanyl]acetate (348 mg, 1.08 mmol) was dissolved in methanol (7.2096 mL) and 2-chloro-N-(3-methylsulfanylphenyl)-5-(trifluoromethyl)pyridine-3-car Treated with voxamide (250 mg, 0.721 mmol) and diammonium carbonate (104 mg, 1.08 mmol) (each added at once). The reaction was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum to give a crude residue. Purified by chromatography on silica, eluting with a gradient of 0 to 30% EtOAc in heptane, 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3- Carboxamide (98.0%) (171 mg, 0.444 mmol, 62% yield) was obtained as a beige solid. ^1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.02 (dd, J = 2.4, 0.8 Hz, 1H), 8.74 - 8.63 (m, 1H), 8.32 (t, J = 1.9 Hz) , 1H), 7.92 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.71 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 4.25 ( s, 1H), 3.07 (d, J = 0.9 Hz, 3H). LC-MS method 1: m/z 378.95 [M+H] ⁺ , (ESI+), RT = 1.00.

Step 3: N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)-2-[4-(trifluoromethyl)phenoxy]pyridine-3-carboxamide: under nitrogen 4-(trifluoromethyl)phenol (63 mg, 0.389 mmol), 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl) in acetonitrile (0.8055 mL) A suspension of pyridine-3-carboxamide (98%, 150 mg, 0.389 mmol) and dipotassium carbonate (81 mg, 0.584 mmol) was heated to 60° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated under vacuum. The filtrate was purified by preparative HPLC (Purification Method 1) to obtain N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)-2-[4-(trifluoromethyl)phenoc. Cy]pyridine-3-carboxamide (97.0%) (97 mg, 0.187 mmol, 48% yield) was obtained as a white solid. ¹ H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.75 - 8.68 (m, 1H), 8.61 - 8.56 (m, 1H), 8.37 (t, J = 1.8 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.89 - 7.81 (m, 2H), 7.75 - 7.66 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 4.24 (s, 1H), 3.06 (s, 3H). LC-MS method 5: m/z 503.9 [M+H] ⁺ , (ESI+), RT = 4.20.

Compound 1565: General Route 4: N-(3-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl) Pyridine-3-carboxamide

Reagents & Conditions: a) 3-aminobenzamide, EDC, pyr; b) 6-(cyclobutoxy)-2-methyl-pyridin-3-ol, K ₂ CO ₃ , ACN, 65°C

Step 1: N-(3-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide: 2-chloro-5-(trifluoro) in pyridine (60 mL) In a solution of methyl)pyridine-3-carboxylic acid (4.00 g, 17.7 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (4.08 g, 21.3 mmol) 3-Aminobenzamide (2.66 g, 19.5 mmol) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was absorbed onto SiO2 and purified by column chromatography (SiO2, 0 to 100% EA in heptane) to give N-(3-carbamoylphenyl)-2-chloro-5-(trifluoromethyl). Pyridine-3-carboxamide (99%) (EV-TXY001-053-001) (4.51 g, 13.1 mmol, 74% yield) was obtained as an off-white solid. LC-MS and ¹ H NMR analysis indicated that this was the desired product. ^1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.16 (t, J = 1.8) Hz, 1H), 8.00 (s, 1H), 7.85 (dd, J = 8.0, 1.3 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.40 (s, 1H). LC-MS method 2: m/z 344.1 [M+H] ⁺ , (ESI+), RT = 0.65.

Step 2: N-(3-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine-3- Carboxamide: N-(3-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide (50 mg, 0.145 mmol) in acetonitrile-anhydrous (0.5 mL) and 6-(cyclobutoxy)-2-methyl-pyridin-3-ol (34 mg, 0.189 mmol) was added dipotassium carbonate (30 mg, 0.218 mmol). The mixture was heated in a pressure vial at 65° C. for 2 hours. The mixture was filtered and concentrated to give a light yellow oil. Purified by preparative HPLC (Purification Method 2). Product-containing fractions were combined to form N-(3-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine- 3-Carboxamide (99%) (57 mg, 0.117 mmol, 81% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the target compound. ^1H NMR (500 MHz, CD ₃ OD) δ 8.55 (s, 2H), 8.19 (s, 1H), 7.96 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.13 (m, 1H), 2.54 - 2.45 (m, 2H), 2.27 (s) , 3H), 2.21 - 2.09 (m, 2H), 1.93 - 1.82 (m, 1H), 1.80 - 1.67 (m, 1H). LC-MS Method 4: m/z 487.2 [M+H] ⁺ , (ESI+), RT = 3.70 LC-MS Method 4.

Compound 1566: General Route 5: N-(4-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl) Pyridine-3-carboxamide

Reagents & Conditions: a) 4-aminobenzamide, EDC, pyridine; b) 6-(cyclobutoxy)-2-methyl-pyridin-3-ol, K ₂ CO ₃ , ACN, 65°C

Step 1: N-(4-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide: 2-chloro-5-(trifluoro) in pyridine (60 mL) In a solution of methyl)pyridine-3-carboxylic acid (4.00 g, 17.7 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (4.08 g, 21.3 mmol) 4-Aminobenzamide (2.66 g, 19.5 mmol) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under vacuum. The residue was absorbed onto SiO2 and purified by column chromatography ( _SiO2 , 0 to 100% EA in heptane) to give (100%) N-(4-carbamoylphenyl)-2-chloro-5-( Trifluoromethyl)pyridine-3-carboxamide (3.33 g, 9.67 mmol, 55% yield) was obtained as an off-white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (500 MHz, CD ₃ OD) δ 8.76 (d, J = 1.7 Hz, 2H), 8.32 (d, J = 2.3 Hz, 1H), 7.85 - 7.79 (m, 2H), 7.73 - 7.67 (m , 2H), 7.57 - 7.50 (m, 1H), 6.59 - 6.52 (m, 1H). LC-MS method 2: m/z 344.0 [M+H] ⁺ , (ESI+), RT = 0.65.

Step 2: N-(4-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluoromethyl)pyridine-3- Carboxamide: N-(4-carbamoylphenyl)-2-chloro-5-(trifluoromethyl)pyridine-3-carboxamide (50 mg, 0.145 mmol) in acetonitrile-anhydrous (0.5 mL) and 6-(cyclobutoxy)-2-methyl-pyridin-3-ol (34 mg, 0.189 mmol) was added dipotassium carbonate (30 mg, 0.218 mmol). The mixture was heated in a pressure vial at 65° C. for 2 hours. The mixture was filtered and concentrated to give an orange oil. Purified by preparative HPLC (Purification Method 2). Product-containing fractions were combined to produce (100%) N-(4-carbamoylphenyl)-2-[[6-(cyclobutoxy)-2-methyl-3-pyridyl]oxy]-5-(trifluorocarbon Methyl)pyridine-3-carboxamide (49 mg, 0.101 mmol, 69%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the target compound. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.58 - 8.51 (m, 2H), 7.94 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 5.13 (p, J = 7.1 Hz, 1H), 2.54 - 2.44 (m, 2H), 2.27 (s, 3H), 2.21 - 2.09 (m, 2H), 1.93 - 1.82 (m, 1H), 1.80 - 1.67 (m, 1H). LC-MS method 4: m/z 487.2 [M+H] ⁺ , (ESI+), RT = 3.68.

Compound 1567: General Route 6: 5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-car Voxamide

Reagents & Conditions: a) 3,4-difluoro-2-methoxy-phenol, Cs ₂ CO ₃ , DMF, 80°C; b) LiOH, water, THF; c) 3-(methylsulfanyl)aniline, EDC, pyridine; d) (NH ₄ ) ₂ CO ₃ , PIDA, MeOH

Step 1: Methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate: Methyl 5-bromo- in DMF-anhydrous (10 mL) Cesium carbonate (1.95 g, 5.99 mmol) in a mixture of 2-chloropyridine-3-carboxylate (1.00 g, 3.99 mmol) and 3,4-difluoro-2-methoxy-phenol (0.83 g, 5.19 mmol). ) was added. The mixture was heated in a pressure vial at 80° C. for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4 x 15 mL) and brine (15 mL). The organic portion was dried (MgSO4), filtered and concentrated to give an orange oil. Purified by FCC (25 g 20 μm, 0 to 15% EA in heptane) to give methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxyl. Rate (95.0%) (EV-TXY001-100-002) (1.15 g, 2.92 mmol, 73% yield) was obtained as a white solid. LC-MS and ¹ H NMR analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.08 - 6.91 (m, 2H), 3.95 (s, 3H) ), 3.82 (d, J = 1.4 Hz, 3H). LC-MS method 2: m/z 374.1 [M+H] ⁺ , (ESI+), RT = 1.00.

Step 2:5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid: THF (8 mL): Methyl 5- in water (2 mL) To a solution of bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (1.15 g, 3.07 mmol), lithium hydroxide (0.17 g, 6.76 mmol) was added. was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3 x 10 mL), dried (MgSO4), filtered and concentrated in vacuo to give 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy ) Pyridine-3-carboxylic acid (97.0%) (1.04 g, 2.79 mmol, 91%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.44 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.07 - 6.93 (m, 2H), 3.82 (d, J = 1.4 Hz, 3H). LC-MS method 2: m/z 360.1 [M]+, (ESI+), RT = 0.86.

Step 3: 5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide: Pyridine-anhydride ( 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (300 mg, 0.833 mmol) and 3-(ethyliminomethylene) in 3 mL) To a solution of amino)-N,N-dimethyl-propan-1-amine hydrochloride (192 mg, 1.00 mmol) was added 3-(methylsulfanyl)aniline (139 mg, 1.00 mmol). The mixture was stirred at room temperature for 0.5 hours. LC-MS analysis indicated that the reaction was complete. The solvent was removed under vacuum and the residue was purified by FCC (10 g, 0 to 30% EA in heptane) to give 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy )-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (92.0%) (402 mg, 0.768 mmol, 92% yield) was obtained as a clear oil. ¹ H NMR and LC-MS analysis indicated that this was the target compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.38 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 2.5 Hz, 1H), 7.72 (t, J = 2.0 Hz, 1H), 7.39 ( m, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.17 - 7.00 (m, 3H), 3.84 (d, J = 1.7 Hz, 3H), 2.49 (s, 3H). LC-MS method 2: m/z 481.1 [M]+, (ESI+), RT = 1.12.

Step 4: 5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide: Phenyl Iodonium diacetate (PIDA) (803 mg, 2.49 mmol) and diammonium carbonate (235 mg, 2.49 mmol) were reacted with 5-bromo-2-(3,4-difluoro-2) in methanol (12 mL). -Methoxy-phenoxy)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (400 mg, 0.831 mmol) was added at room temperature, and the reaction was stirred at room temperature for 1 hour. The solvent was removed under vacuum and the residue was purified by FCC (10 g, 0 to 100% EA in heptane) to give 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy )-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (88.0%) (328 mg, 0.563 mmol, 68% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the target compound. 30 mg was purified by preparative HPLC (Purification Method 2). Product fractions were combined, concentrated under reduced pressure, and the resulting residue was lyophilized from MeCN-water (1:1) to obtain 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy )-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (100.0%) (17 mg, 0.0332 mmol, 4.0%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the target compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (t, J = 2.0 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.31 (d, J = 2.5 Hz, 1H), 7.98 ( m, 1H), 7.80 (m, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.17 - 7.00 (m, 2H), 3.84 (d, J = 1.7 Hz, 3H), 3.17 (s, 3H) ). LC-MS method 7: m/z 512.2 [M]+, (ESI+), RT = 3.33.

Compound 1568: General Route 7: 5-Bromo-N-(3-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide

Reagents & Conditions: a) Cs ₂ CO ₃ , DMF, 80°C; b) LiOH, water, THF; c) 3-aminobenzamide, EDC, pyridine

Step 1: Methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate: Methyl 5-bromo- in DMF-anhydrous (10 mL) Cesium carbonate (1.95 g, 5.99 mmol) in a mixture of 2-chloropyridine-3-carboxylate (1.00 g, 3.99 mmol) and 3,4-difluoro-2-methoxy-phenol (0.83 g, 5.19 mmol). ) was added. The mixture was heated in a pressure vial at 80° C. for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4 x 15 mL) and brine (15 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give an orange oil. Purified by FCC (25 g 20 μm, 0 to 15% EA in heptane) to give methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxyl. Rate (95.0%) (1.15 g, 2.92 mmol, 73%) was obtained as a white solid. LC-MS and ¹ H NMR analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.08 - 6.91 (m, 2H), 3.95 (s, 3H) ), 3.82 (d, J = 1.4 Hz, 3H). LC-MS method 2: m/z 374.1 [M+H] ⁺ , (ESI+), RT = 1.00.

Step 2: 5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid: THF (8 mL): Methyl 5- in water (2 mL) To a solution of bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (1.15 g, 3.07 mmol), lithium hydroxide (0.17 g, 6.76 mmol) was added. was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3 x 10 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to give 5-bromo-2-(3,4-difluoro-2-methoxy-phenok). C)Pyridine-3-carboxylic acid (97.0%) (1.04 g, 2.79 mmol, 91%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.44 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.07 - 6.93 (m, 2H), 3.82 (d, J = 1.4 Hz, 3H). LC-MS method 2: m/z 360.1 [M] ⁺ , (ESI+), RT = 0.86.

Step 3: 5-Bromo-N-(3-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide: Pyridine-anhydride ( 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (300 mg, 0.833 mmol) and 3-(ethyliminomethylene) in 3 mL) To a solution of amino)-N,N-dimethyl-propan-1-amine hydrochloride (192 mg, 1.00 mmol) was added 3-aminobenzamide (139 mg, 1.00 mmol). The mixture was stirred at room temperature for 0.5 hours. Solvent was removed and the residue was purified by FCC (10 g, 0 to 100% EA in heptane) to give 5-bromo-N-(3-carbamoylphenyl)-2-(3,4-difluor Ro-2-methoxy-phenoxy)pyridine-3-carboxamide (92.0%) (385 mg, 0.741 mmol, 89%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. 30 mg was further purified by preparative HPLC (Purification Method 2). Product fractions were combined, concentrated under reduced pressure, and the resulting residue was lyophilized from MeCN-water (1:1) to give 5-bromo-N-(3-carbamoylphenyl)-2-(3,4- Difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (100.0%) (23 mg, 0.0481 mmol, 5.8%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.42 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.16 (t, J = 2.0 Hz, 1H), 7.92 ( m, 1H), 7.70 - 7.63 (m, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.13 (m, 1H), 7.10 - 7.02 (m, 1H), 3.84 (d, J = 1.7 Hz) , 3H). LC-MS method 4: m/z 478.1 [M]+, (ESI+), RT = 3.36.

Compound 1569: General Route 8: 5-Bromo-N-(4-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide

Reagents & Conditions: a) Cs ₂ CO ₃ , DMF, 80°C; b) LiOH, water, THF; c) 4-aminobenzamide, EDC, pyridine

Step 1: Methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate: Methyl 5-bromo- in DMF-anhydrous (10 mL) Cesium carbonate (1.95 g, 5.99 mmol) in a mixture of 2-chloropyridine-3-carboxylate (1.00 g, 3.99 mmol) and 3,4-difluoro-2-methoxy-phenol (0.83 g, 5.19 mmol). ) was added. The mixture was heated in a pressure vial at 80° C. for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4 x 15 mL) and brine (15 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give an orange oil. Purified by FCC (25 g 20 μm, 0 to 15% EA in heptane) to give methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxyl. Rate (95.0%) (1.15 g, 2.92 mmol, 73% yield) was obtained as a white solid. LC-MS and ¹ H NMR analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.08 - 6.91 (m, 2H), 3.95 (s, 3H) ), 3.82 (d, J = 1.4 Hz, 3H). LC-MS method 2: m/z 374.1 [M+H] ⁺ , (ESI+), RT = 1.00.

Step 2: 5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid: THF (8 mL): Methyl 5- in water (2 mL) To a solution of bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (1.15 g, 3.07 mmol), lithium hydroxide (0.17 g, 6.76 mmol) was added. was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3 x 10 mL), dried (MgSO4), filtered and concentrated in vacuo to give 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy ) Pyridine-3-carboxylic acid (97.0%) (1.04 g, 2.79 mmol, 91%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.44 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.07 - 6.93 (m, 2H), 3.82 (d, J = 1.4 Hz, 3H). LC-MS method 2: m/z 360.1 [M]+, (ESI+), RT = 0.86.

Step 3: 5-Bromo-N-(4-carbamoylphenyl)-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide: Pyridine-anhydride ( 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (300 mg, 0.833 mmol) and 3-(ethyliminomethylene) in 3 mL) To a solution of amino)-N,N-dimethyl-propan-1-amine hydrochloride (192 mg, 1.00 mmol) was added 4-aminobenzamide (139 mg, 1.00 mmol). The mixture was stirred at room temperature for 0.5 hours. LC-MS analysis indicated that the reaction was complete. The solvent was removed and the residue was purified by FCC (10 g, 0 to 100% EA in heptane then 0 to 5% MeOH in EA) to give 5-bromo-N-(4-carbamoylphenyl)- 2-(3,4-Difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (95.0%) (298 mg, 0.592 mmol, 71%) was obtained as a white solid. 1H-19F-NMR and LC-MS analysis indicated that this was the desired product. An additional 30 mg was purified by preparative HPLC (Purification Method 2), freeze-dried, and then 5-bromo-N-(4-carbamoylphenyl)-2-(3,4-difluoro-2-mer). Toxy-phenoxy)pyridine-3-carboxamide (100.0%) (21 mg, 0.0439 mmol, 5.3%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.85 - 7.78 (m , 2H), 7.13 (m, 1H), 7.05 (m, 1H), 3.84 (d, J = 1.7 Hz, 3H). LC-MS method 3: m/z 478.2 [M]+, (ESI+), RT = 3.36

Compound 1570: General Route 9: 5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-pyridine-3-carboxamide

Reagents & Conditions: a) Cs ₂ CO ₃ , DMF, 80°C; b) LiOH, water, THF; c) Pyridazin-4-amine, EDC, pyridine

Step 1: Methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate: Methyl 5-bromo- in DMF-anhydrous (10 mL) Cesium carbonate (1.95 g, 5.99 mmol) in a mixture of 2-chloropyridine-3-carboxylate (1.00 g, 3.99 mmol) and 3,4-difluoro-2-methoxy-phenol (0.83 g, 5.19 mmol). ) was added. The mixture was heated in a pressure vial at 80° C. for 3 hours. The mixture was diluted with ethyl acetate (30 mL) and washed with water (4 x 15 mL) and brine (15 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give an orange oil. Purified by FCC (25 g 20 μm, 0 to 15% EA in heptane) to give methyl 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxyl. Rate (95.0%) (1.15 g, 2.92 mmol, 73% yield) was obtained as a white solid. LC-MS and ¹ H NMR analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 7.08 - 6.91 (m, 2H), 3.95 (s, 3H) ), 3.82 (d, J = 1.4 Hz, 3H). LC-MS method 2: m/z 374.1 [M+H] ⁺ , (ESI+), RT = 1.00.

Step 2: 5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid: THF (8 mL): Methyl 5- in water (2 mL) To a solution of bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (1.15 g, 3.07 mmol), lithium hydroxide (0.17 g, 6.76 mmol) was added. was added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3 x 10 mL), dried (MgSO4), filtered and concentrated in vacuo to give 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy ) Pyridine-3-carboxylic acid (97.0%) (1.04 g, 2.79 mmol, 91%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.44 (d, J = 2.6 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.07 - 6.93 (m, 2H), 3.82 (d, J = 1.4 Hz, 3H). LC-MS method 2: m/z 360.1 [M]+, (ESI+), RT = 0.86.

Step 3: 5-Bromo-2-(3,4-difluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-pyridine-3-carboxamide: Pyridine-anhydride (1.65 mL) 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (165 mg, 0.458 mmol) and 3-(ethyliminomethyleneamino) )-N,N-dimethyl-propan-1-amine To a solution of hydrochloride (105 mg, 0.550 mmol) was added pyridazin-4-amine (52 mg, 0.550 mmol). The mixture was stirred at room temperature for 1 hour. LC-MS analysis (EV-TXY001-107-IPC1) indicated that the reaction was complete. The solvent was removed and the residue was purified by FCC (10 g, 0 to 100% EA in heptane) to give 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy)- N-Pyridazin-4-yl-pyridine-3-carboxamide (146 mg, 0.334 mmol, 73% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the target compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.41 (dd, J = 2.7, 1.0 Hz, 1H), 9.07 (dd, J = 6.0, 1.0 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H) ), 8.34 (d, J = 2.5 Hz, 1H), 8.23 (dd, J = 6.0, 2.7 Hz, 1H), 7.16 - 7.00 (m, 2H), 3.83 (d, J = 1.7 Hz, 3H). LC-MS method 3: m/z 437.1 [M] ⁺ , (ESI+), RT = 3.24.

Compound 1571: General Route 10: Methyl 3-[[2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bi Cyclo[1.1.1]pentane-1-carboxylate

Reagents & Conditions: a) 3-Aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride, EDC, pyr; b) Difluoro-2-methoxy-phenol, K ₂ CO ₃ , ACN, 65°C

Step 1: Methyl 3-[2-chloro-5-(trifluoromethyl)pyridine-3-carbonyl]bicyclo[1.1.1]pentane-1-carboxylate: 2-chloro in pyridine (1.5 mL) -5-(trifluoromethyl)pyridine-3-carboxylic acid (100 mg, 0.443 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (102 mg , 0.532 mmol), methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (79 mg, 0.443 mmol) was added. The mixture was stirred at room temperature for 1 hour. LC-MS analysis indicated that the reaction was mostly complete. The solvent was removed and the residue was purified by FCC (10 g, 0 to 40% EA in heptane) to give methyl 3-[[2-chloro-5-(trifluoromethyl)pyridine-3-carbonyl]amino. ]Bicyclo[1.1.1]pentane-1-carboxylate (100%) (126 mg, 0.361 mmol, 82%) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.82 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 3.72 (s, 3H), 2.46 (s, 6H). LC-MS method 2: m/z 349.0 [M+H] ⁺ , (ESI+), RT = 0.76.

Step 2: Methyl 3-[[2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane -1-Carboxylate: Methyl 3-[[2-chloro-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane in acetonitrile-anhydrous (0.5 mL) Add dipotassium carbonate (30 mg, 0.215 mmol) to a mixture of -1-carboxylate (50 mg, 0.143 mmol) and 3,4-difluoro-2-methoxy-phenol (30 mg, 0.186 mmol). did. The mixture was heated in a pressure vial at 65° C. for 3 hours. LC-MS analysis indicated that the reaction was complete. The mixture was filtered and concentrated to give a clear oil. Purified by FCC (10 g, 0 to 20% EA in heptane) to give methyl 3-[[2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl) Pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1-carboxylate (99.0%) (55 mg, 0.115 mmol, 80% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (dd, J = 2.4, 0.9 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 7.14 - 7.03 (m, 2H), 3.85 (d) , J = 1.8 Hz, 3H), 3.71 (s, 3H), 2.47 (s, 6H). LC-MS method 6: m/z 473.3 [M+H] ⁺ , (ESI+), RT = 3.98.

Compound 1572: General Route 11: 2-(4-Cyano-2-methoxy-phenoxy)-N-(1-oxidopyridin-1-ium-3-yl)-5-(trifluoromethyl) Pyridine-3-carboxamide

Reagents & Conditions: a) 4-hydroxy-3-methoxybenzonitrile, K ₂ CO ₃ , ACN, 80°C; b) LiOH, water, THF; c) pyridin-3-amine, EDC, pyridine d) MCPBA, DCM

Step 1: Methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate: 2-chloro- in acetonitrile-anhydrous (2.5 mL) A mixture of 5-trifluoromethyl-nicotinic acid methyl ester (100 mg, 0.417 mmol), 4-hydroxy-3-methoxybenzonitrile (93 mg, 0.624 mmol) and potassium carbonate (87 mg, 0.629 mmol) was reduced under reduced pressure. The vial was stirred at 80°C for 1 hour. LC-MS analysis indicated that the reaction was mostly complete. The mixture was filtered and concentrated to give a clear oil. Purified by FCC (5 g, 0 to 40% EA in heptane) to give methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate. (100.0%) (142 mg, 0.403 mmol, 97%) was obtained as a white semi-solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, DMSO-d6) δ 8.73 (m, 1H), 8.60 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.53 (dd, J = 8.2 , 1.8 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 3.91 (s, 3H), 3.74 (s, 3H). LC-MS method 2: m/z 353.1 [M+H] ⁺ , (ESI+), RT = 0.94.

Step 2: 2-(4-Cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid: THF (1.8 mL): Methyl 2 in water (0.4 mL) In a solution of -(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (142 mg, 0.403 mmol), lithium hydroxide (10 mg, 0.403 mmol) ) was added, and the mixture was stirred at room temperature for 1 hour. LC-MS analysis indicated that the reaction was complete. The mixture was diluted with water (5 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3 x 5 mL), dried (MgSO ₄ ), filtered, and concentrated in vacuo to give 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluorocarbons). Romethyl)pyridine-3-carboxylic acid (100.0%) (134 mg, 0.396 mmol, 98% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, DMSO-d6) δ 8.68 (m, 1H), 8.55 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.53 (dd, J = 8.2) , 1.8 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 3.75 (s, 3H). LC-MS method 2: m/z 339.1 [M+H] ⁺ , (ESI+), RT = 0.79.

Step 3: 2-(4-Cyano-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide: Pyridine (0.8 mL) Among 2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (70 mg, 0.207 mmol) and 3-(ethyliminomethyleneamino) To a solution of -N,N-dimethyl-propan-1-amine hydrochloride (48 mg, 0.248 mmol) was added pyridin-3-amine (21 mg, 0.228 mmol). The mixture was stirred at room temperature for 1 hour. LC-MS analysis indicated that the reaction was complete. The solvent was removed and the residue was purified by FCC (5 g, 0 to 70% EA in heptane) to give 2-(4-cyano-2-methoxy-phenoxy)-N-(3-pyridyl) -5-(Trifluoromethyl)pyridine-3-carboxamide (98.0%) (75 mg, 0.177 mmol, 86% yield) was obtained as a white solid. 1H-19F-NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.86 (d, J = 2.5 Hz, 1H), 8.67 (m, 1H), 8.58 (d, J = 2.5 Hz, 1H), 8.35 (dd, J = 4.7, 1.5 Hz, 1H), 8.17 (dt, J = 8.5, 1.8 Hz, 1H), 7.69 (m, 1H), 7.58 - 7.48 (m, 2H), 7.43 (dd, J = 8.3, 4.7 Hz, 1H), 3.76 (s, 3H). LC-MS method 2: m/z 415.2 [M+H] ⁺ , (ESI+), RT = 0.78.

Step 4: 2-(4-Cyano-2-methoxy-phenoxy)-N-(1-oxidopyridin-1-ium-3-yl)-5-(trifluoromethyl)pyridine-3- Carboxamide: 2-(4-cyano-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)pyridine-3 in DCM (3 mL) at 0°C. A solution of -carboxamide (75 mg, 0.181 mmol) was treated with 3-chloroperoxybenzoic acid (73%, 45 mg, 0.190 mmol), then allowed to warm to room temperature and stirred for 0.5 h. LC-MS analysis indicated that the reaction was mostly complete. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Purification Method 2) to give a white solid (about 80 mg, containing mCBA). Further purification (Purification Method 1) gave 2-(4-cyano-2-methoxy-phenoxy)-N-(1-oxidopyridin-1-ium-3-yl)-5-(trifluoromethyl ) Pyridine-3-carboxamide (100.0%) (13 mg, 0.0302 mmol, 17% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 9.10 (m, 1H), 8.58 (m, 1H), 8.54 (m, 1H), 8.19 - 8.13 (m, 1H), 7.81 (m, 1H), 7.58 - 7.41 (m, 4H), 3.80 (s, 3H). LC-MS method 4: m/z 431.2 [M+H] ⁺ , (ESI+), RT = 2.63.

Example 87

Exemplary compounds of the invention are listed in Table 15 using one of the general routes described above.

Table 15

Example 88

Compound 1716: N-[3-(N-Acetyl-S-methyl-sulfonimidoyl)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine- 3-Carboxamide

(R)-2-(4-Fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl) in DCM (1.0697 mL) at room temperature. To a solution of pyridine-3-carboxamide (50 mg, 0.107 mmol) was added pyridine (0.017 mL, 0.214 mmol) and acetic anhydride (0.012 mL, 0.128 mmol). The mixture was stirred overnight at room temperature under an atmosphere of nitrogen. The reaction was concentrated under a stream of nitrogen. Loaded onto a 10g Spa Duo cartridge in DCM (3x 0.5mL) and then eluted with 0-50% EtOAc/Hepto. Relevant fractions were concentrated to give N-[3-(N-acetyl-S-methyl-sulfonimidoyl)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl) Pyridine-3-carboxamide (98.0%) (45 mg, 0.0873 mmol, 82%) was obtained. ¹ H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.67 - 8.63 (m, 1H), 8.57 - 8.53 (m, 1H), 8.41 - 8.36 (m, 1H), 8.00 - 7.94 ( m, 1H), 7.70 - 7.63 (m, 2H), 7.28 - 7.22 (m, 1H), 7.22 - 7.15 (m, 1H), 7.13 - 7.05 (m, 1H), 3.40 (s, 3H), 2.08 ( s, 3H), 1.96 (s, 3H). LC-MS method 4: m/z 510.1 [M+H] ⁺ , (ESI+), RT = 3.51.

Example 89

Compound 1717: N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-car Voxamide

(R)-2-(4-Fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide ( 50 mg, 0.107 mmol), copper(2+) diacetate (29 mg, 0.160 mmol) and methylboronic acid (13 mg, 0.214 mmol) were suspended in 1,4-dioxane-anhydride (0.8557 mL) and washed with air. and stirred at room temperature for 5 minutes. Pyridine (0.017 mL, 0.214 mmol) was then added and the vessel was sealed and heated to 100° C. for 40 min. The reaction mixture was diluted with water (˜1.5 mL) and DCM (3 mL), shaken vigorously, and then the mixture was filtered through a PTFE phase separator. The aqueous layer was re-extracted with DCM (2 mL) and the layers were separated. The combined organic portions were concentrated under a gentle stream of nitrogen. The crude material was purified by preparative HPLC (Purification Method 2) to give N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-(4-fluoro-2-methyl-phenoxy)-5. -(Trifluoromethyl)pyridine-3-carboxamide was obtained as a white powder (43 mg, 51%). ^1H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.66 (dd, J = 2.5, 1.1 Hz, 1H), 8.57 - 8.53 (m, 1H), 8.30 (t, J = 1.9 Hz) , 1H), 7.95 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.26 (dd, J = 8.9, 5.1 Hz, 1H), 7.20 (dd, J = 9.7, 3.2 Hz, 1H), 7.11 (td, J = 8.5, 3.2 Hz, 1H), 3.11 (s, 3H), 2.49 (s, 3H), 2.09 (s) , 3H). LC-MS method 6: m/z 482.3 [M+H] ⁺ , (ESI+), RT = 3.62.

Example 90

Compound 1718: 2-(3-methylsulfonylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide

2-(3-methylsulfanylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (48 mg, 0.0997 mmol) was dissolved in methanol (1.0 mL). ), treated with potassium hydrogen sulfate (33 mg, 0.219 mmol), and the resulting mixture was stirred at room temperature. After 24 hours, additional potassium hydrogen sulfate (40 mg, 0.267 mmol) was added and the reaction was stirred at room temperature for a further 24 hours. The reaction was diluted with DCM (25 mL) and NaHCO3 (saturated aqueous solution, 25 mL). Stir vigorously for 5 minutes and filter through a phase separator. The aqueous portion was re-extracted with DCM (x1) and filtered. The combined organic portions were concentrated under vacuum to a white solid. 2-(3-methylsulfonylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3 by column treatment with 0-100% EtOAc/Hep on a 10g Spa Duo cartridge. -Carboxamide (98.0%) (33 mg, 0.0629 mmol, 63%) was obtained. ^1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.74 - 8.71 (m, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.41 - 8.38 (m, 1H), 7.97 (dt, J = 7.3, 1.8 Hz, 1H), 7.91 - 7.84 (m, 2H), 7.76 (t, J = 7.9 Hz, 1H), 7.73 - 7.64 (m, 3H), 3.27 (s, 3H), 3.22 (s, 3H). LC-MS method 4: m/z 515.1 [M+H] ⁺ , (ESI+), RT = 3.06.

Example 91

Compound 1719: tert-Butyl (R)-(2-(((3-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinamido)phenyl)(methyl )(oxo)-λ ⁶ -sulfanylidene)amino)-2-oxoethyl)(methyl)carbamate

N-(tert-butoxycarbonyl)-N-methylglycine (18 mg, 0.0941 mmol) and N-(tert-butoxycarbonyl)-N-methylglycine (18 mg, 0.0941 mmol) were incubated at room temperature in DCM ( 0.4279 mL) followed by the addition of N-ethyl-N-(propan-2-yl)propan-2-amine (0.036 mL, 0.205 mmol). The suspension was stirred at room temperature for 5-10 minutes, then (R)-2-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5- (Trifluoromethyl)nicotinamide (100%, 40 mg, 0.0856 mmol) was added in 1 portion. The resulting suspension was stirred at room temperature. The reaction was concentrated under a stream of nitrogen. Loaded onto a 10g Spa Duo cartridge in DCM (3x 0.5mL) and then eluted with 0-50% EtOAc/Hepto. The relevant fractions were concentrated to give a colorless glass (54 mg, 99%). ^1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.68 - 8.64 (m, 1H), 8.57 - 8.51 (m, 1H), 8.50 - 8.43 (m, 1H), 8.01 - 7.92 ( m, 1H), 7.71 - 7.63 (m, 2H), 7.26 (dd, J = 8.9, 5.0 Hz, 1H), 7.20 (dd, J = 9.3, 3.1 Hz, 1H), 7.11 (td, J = 8.5, 3.1 Hz, 1H), 3.97 - 3.77 (m, 2H), 3.47 (s, 3H), 2.80 - 2.72 (m, 3H), 2.09 (s, 3H), 1.36 (s, 4H), 1.28 (s, 5H) ). LC-MS method 6: m/z 639.3 [M+H] ⁺ , (ESI+), RT = 4.15.

Example 92

Compound 1720: (R)-2-(4-fluoro-2-methylphenoxy)-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-5-(tri Fluoromethyl)nicotinamide

tert-Butyl (R)-(2-(((3-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinamido)phenyl in DCM (1.0 mL) )(methyl)(oxo)-λ ⁶ -sulfanylidene)amino)-2-oxoethyl)(methyl)carbamate (61 mg, 0.0955 mmol) in phosphoric acid (85% wt) in water at room temperature ( 85%, 0.044 mL, 0.382 mmol) (12 μL added) was added. The mixture was stirred vigorously at room temperature for 2-3 hours. The reaction mixture was diluted with NaOH (2N, 5mL) and extracted twice with DCM (2x 5mL). Each extract was filtered through a phase separator cartridge and concentrated to brown gum. The crude material was loaded onto a 10g Spa Duo cartridge and eluted with 0-100% EtOAc/Hep followed by 0-50% MeOH/EtOAc to give (R)-2-(4-fluoro-2-methylphenoxy)- N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide (93.5%) (36 mg, 0.0625 mmol, 65% yield) Obtained as a light brown powder. ¹ H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.70 - 8.65 (m, 1H), 8.58 - 8.54 (m, 1H), 8.47 - 8.41 (m, 1H), 8.02 - 7.96 ( m, 1H), 7.74 - 7.65 (m, 2H), 7.27 (dd, J = 8.9, 5.0 Hz, 1H), 7.21 (dd, J = 9.3, 3.1 Hz, 1H), 7.12 (td, J = 8.5, 3.3 Hz, 1H), 3.46 (s, 3H), 3.20 (s, 2H), 2.24 (s, 3H), 2.10 (s, 3H). LC-MS method 6: m/z 539.2 [M+H] ⁺ , (ESI+), RT = 3.42.

Example 93

Compound 1721: N-(3-carbamoyl-1-bicyclo[1.1.1]fentanyl)-2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoro Methyl)pyridine-3-carboxamide

Methyl 3-[[2-(4-cyano-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane-1- The carboxylate (34 mg, 0.0737 mmol) was dissolved in IPA (0.257 mL) and diluted with 14.5 M ammonium hydroxide (1.0 mL, 14.5 mmol). The solution was stirred in a pressure vial at 40° C. for 2 hours. LC-MS analysis indicated that the reaction was mostly complete. The solvent was removed, and the residue was purified by preparative HPLC (Purification Method 2) to give N-(3-carbamoyl-1-bicyclo[1.1.1]fentanyl)-2-(4-cyano-2 -Methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (100.0%) (13 mg, 0.0291 mmol, 40% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.47 (s, 2H), 7.54 (d, J = 1.3 Hz, 1H), 7.51 - 7.41 (m, 2H), 3.81 (s, 3H), 2.45 (s) , 6H). LC-MS method 6: m/z 447.3 [M+H] ⁺ , (ESI+), RT = 2.96.

Example 94

Compound 1722: N-(3-carbamoyl-1-bicyclo[1.1.1]fentanyl)-2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoro Methyl)pyridine-3-carboxamide

Methyl 3-[[2-(3,4-difluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbonyl]amino]bicyclo[1.1.1]pentane -1-Carboxylate (35 mg, 0.0741 mmol) was dissolved in IPA (0.2584 mL) and diluted with 14.5 M ammonium hydroxide (0.50 mL, 7.3 mmol). The solution was stirred in a pressure vial at 40° C. for 1 hour. LC-MS analysis indicated that the reaction was mostly complete. Purified by preparative HPLC (Purification Method 2) to obtain N-(3-carbamoyl-1-bicyclo[1.1.1]fentanyl)-2-(3,4-difluoro-2-methoxy-phenok Si)-5-(trifluoromethyl)pyridine-3-carboxamide (100.0%) (16 mg, 0.0350 mmol, 47% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the target compound. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.51 (m, 1H), 8.44 (m, 1H), 7.19 - 7.03 (m, 2H), 3.85 (d, J = 1.8 Hz, 3H), 2.45 (s) , 6H). LC-MS method 6: m/z 458.2 [M+H] ⁺ , (ESI+), RT = 3.23.

Example 95

Compound 1723: 5-Cyano-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide

Palladium acetate (8.8 mg, 0.0390 mmol) was dissolved as (LTGO 0001070) 5-bromo-2-(3,4-difluoro-2-methoxy-phenoxy) in DMF (2 mL) and water (2 mL). -N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (200 mg, 0.390 mmol), potassium hexakis(cyano-kappaC)ferrate(4-) hydrate (4:1 :3) Degassing of (82 mg, 0.195 mmol), sodium carbonate (41 mg, 0.390 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (42 mg, 0.0781 mmol) It was added to the stirred solution. The reaction mixture was heated at 70° C. for 3 hours. LC-MS analysis indicated that the reaction was complete. Diluted with water (10 mL) and extracted with ethyl acetate (3 x 8 mL). The organic portion was dried (MgSO4), filtered and concentrated to give an orange oil. Purified by preparative HPLC (Purification Method 2), 5-cyano-2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl] Pyridine-3-carboxamide (100.0%) (59 mg, 0.129 mmol, 33% yield) was obtained as a white solid. ¹ H and ¹⁹ F NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.60 (d, J = 2.3 Hz, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.45 (t, J = 2.0 Hz, 1H), 8.03 - 7.95 (m, 1H), 7.81 (m, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.17 - 7.10 (m, 1H), 7.10 - 7.03 (m, 1H), 3.85 (d, J = 1.8 Hz, 3H), 3.17 (s, 3H). LC-MS method 7: m/z 459.2 [M+H] ⁺ , (ESI+), RT = 2.87.

Example 96

Compound 1724: N-(3-carbamoylphenyl)-5-cyano-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide

Palladium acetate (4.7 mg, 0.0209 mmol) was reacted with 5-bromo-N-(3-carbamoylphenyl)-2-(3,4-difluoro-2) in DMF (1.5 mL) and water (1.5 mL). -methoxy-phenoxy)pyridine-3-carboxamide (100 mg, 0.209 mmol), potassium hexakis(cyano-kappaC)ferrate(4-) hydrate (4:1:3) (44 mg, 0.105 mmol), sodium carbonate (22 mg, 0.209 mmol) and [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane (23 mg, 0.0418 mmol). . The reaction mixture was heated at 75° C. for 4 hours. LC-MS analysis indicated that starting material remained, but the reaction profile became more messy and the reaction was stopped. Diluted with water (10 mL) and extracted with ethyl acetate (3 x 8 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give an orange oil. Purification by preparative HPLC (Purification Method 2) gave 15 mg as a white solid. LC-MS analysis indicated that this was the target compound but was not clean (84% at 215 nm). Further purification by preparative HPLC (Purification Method 1) gave 10.2 mg as a white solid. LC-MS analysis showed only 82% at 215 nm. Additionally, preparative HPLC (Waters Sunfire C18 column (19 mm ; B = 0.1% formic acid in acetonitrile) in 1.9 min followed by a gradient of 35 - 95% B over 16 min followed by a hold for 2 min. UV spectra were recorded at 215 nm using a Gilson detector. N-(3-carbamoylphenyl)-5-cyano-2-(3,4-difluoro-2-methoxy-phenoxy)pyridine-3-carboxamide (100.0%) (6.8 mg, 0.016 mmol, 7.7% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis showed that this was the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.62 (s, 1H), 8.92 (d) , J = 2.3 Hz, 1H), 8.51 (d, J = 2.3 Hz, 1H), 8.08 (t, J = 1.9 Hz, 1H), 8.02 - 7.96 (m, 1H), 7.60 (m, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.10 - 6.94 (m, 2H), 6.14 (s, 1H), 5.58 (s, 1H), 3.93 (d, J = 2.8 Hz, 3H). LC-MS method 4: m/z 425.5 [M+H] ⁺ , (ESI+), RT = 2.93.

Example 97

Compound 1725: 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(3-oxabicyclo[4.1.0]heptane-6 -1) Pyridine-3-carboxamide

5-Bromo-2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (40 mg, 0.0798 mmol), potassium; Trifluoro(3-oxabicyclo[4.1.0]heptan-6-yl)boranoid (20 mg, 0.0957 mmol), cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (5.9 mg, 7.98 μmol) ) and cesium carbonate (52 mg, 0.160 mmol) were suspended in toluene (0.8 mL) and water (0.2 mL) and then degassed for 5 minutes. The mixture was heated to 80° C. for 2 hours. LC-MS analysis indicated that the starting material was consumed. The mixture was diluted with ethyl acetate (5 mL), filtered, and concentrated to give a brown oil. Purified by preparative HPLC (standard methods), 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-(3-oxabicyclo [4.1.0]heptan-6-yl)pyridine-3-carboxamide (100.0%) (20 mg, 0.0386 mmol, 48% yield) was obtained as an off-white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (m, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.14 (d, J = 2.5 Hz, 1H), 8.01 (m, 1H), 7.83 - 7.76 (m, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.53 - 7.39 (m, 3H), 4.10 (dd, J = 11.4, 4.5 Hz, 1H), 3.92 (m, 1H) , 3.81 (s, 3H), 3.58 (m, 1H), 3.54 - 3.41 (m, 1H), 3.17 (s, 3H), 2.18 (m, 1H), 2.01 (m, 1H), 1.42 (m, 1H) ), 1.12 (m, 1H), 1.00 (t, J = 5.4 Hz, 1H). LC-MS method 4: m/z 519.2 [M+H] ⁺ , (ESI+), RT = 2.69.

Example 98

Compound 1726: 2-(4-Cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(3-methylsulfanylphenyl)pyridine -3-carboxamide

Reagents & Conditions: a) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran, Pd(OAc ) ₂ , dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane, Na ₃ PO ₄ , dioxane, 80°C; b) PIDA, (NH ₄ ) ₂ CO ₃ , MeOH

Step 1: 2-(4-Cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(3-methylsulfanylphenyl)pyridine -3-Carboxamide: 5-bromo-2-(4-cyano-2-methoxy-phenoxy)-N-(3) in 1,4-dioxane (0.8 mL) and water (0.2 mL) -methylsulfanylphenyl)pyridine-3-carboxamide (50 mg, 0.106 mmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (5.1 mg, 0.0106 mmol) ), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (25 mg, 0.117 mmol) and A mixture of tripotassium phosphate (68 mg, 0.319 mmol) was degassed with nitrogen for 5 minutes, and then palladium(2+) diacetate (2.4 mg, 0.0106 mmol) was added. The mixture was heated in a pressure vial to 80° C. for 8 hours. LC-MS analysis indicated that the reaction was complete. Diluted with ethyl acetate (8 mL) and washed with water (5 mL) and brine (5 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give a brown oil. Purified by FCC (5 g, 0 to 30% EA in heptane) to give 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4- 1)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (37.0%) (34 mg, 0.0266 mmol, 25% yield) was obtained as an off-white solid, 34 mg. LC-MS analysis showed that this was about a 5:4 mixture of hydrodehalogenation by-product (1.06 min) and desired product (1.11 min). It was used for oxidation without further purification. LC-MS method 2: m/z 474.2 [M+H] ⁺ , (ESI+), RT = 1.11.

Step 2: 2-(4-Cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-[3-(methylsulfonimidoyl) Phenyl]pyridine-3-carboxamide: Phenyl iodonium diacetate (PIDA) (29 mg, 0.0912 mmol) and diammonium carbonate (8.6 mg, 0.0912 mmol) were dissolved in 2-(4-cyanol) in methanol (0.4 mL). Nor-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)-N-(3-methylsulfanylphenyl)pyridine-3-carboxamide (40% , 36 mg, 0.0304 mmol) was added to the solution, and the reaction was stirred at room temperature for 1 hour. LC-MS analysis indicated that the reaction was complete. The solvent was removed, and the residue was purified by preparative HPLC (Purification Method 1), freeze-dried, and then 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H. -Pyran-4-yl)-N-[3-(methylsulfonimidoyl)phenyl]pyridine-3-carboxamide (100.0%) (8.0 mg, 0.0159 mmol, 52% yield) was obtained as a white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.39 (m, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.20 (d, J = 2.5 Hz, 1H), 7.94 (m, 1H), 7.69 - 7.66 (m, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.9 Hz) , 1H), 7.45 (d, J = 8.2 Hz, 1H), 6.38 (s, 1H), 4.23 (d, J = 2.8 Hz, 2H), 4.21 (s, 1H), 3.82 (t, J = 5.4 Hz) , 2H), 3.75 (s, 3H), 3.05 (d, J = 1.0 Hz, 3H). LC-MS method 6: m/z 505.3 [M+H] ⁺ , (ESI+), RT = 1.11.

Example 99

Compound 1727: 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-tetrahydropyran-4-yl-pyridine-3-carboxyx amides

Reagents & Conditions: a) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran, Pd(OAc ) ₂ , dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane, Na ₃ PO ₄ , dioxane, 80°C; b) H ₂ , Pd (10%), EtOH; c) LiOH, water, THF; d) 3-(methylsulfanyl)aniline, EDC, pyr; e) PIDA, (NH ₄ ) ₂ CO ₃ , MeOH

Step 1: Methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)pyridine-3-carboxylate: 1,4 -Methyl 5-bromo-2-(4-cyano-2-methoxy-phenoxy)pyridine-3-carboxylate (250 mg, 0.688 mmol) in dioxane (5 mL) and water (1.5 mL) , dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (33 mg, 0.0688 mmol), 4-(4,4,5,5-tetramethyl-1,3, A mixture of 2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (217 mg, 1.03 mmol) and tripotassium phosphate (438 mg, 2.07 mmol) was degassed with nitrogen for 5 minutes. Afterwards, palladium (2+) diacetate (15 mg, 0.0688 mmol) was added. The mixture was heated to 80° C. in a pressure vial for 2 hours. LC-MS analysis indicated that the reaction was complete. Diluted with ethyl acetate (20 mL) and washed with water (8 mL) and brine (8 mL). The organic portion was dried (MgSO4), filtered and concentrated. Purified by FCC (5 g, 0 to 30% EA in heptane) to give methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4 -yl)pyridine-3-carboxylate (99.0%) (249 mg, 0.673 mmol, 98% yield) was obtained as a beige foam. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.30 (d, J = 2.3 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H), 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.25 - 7.21 (m, 2H), 6.17 (m, 1H), 4.32 (q, J = 2.8 Hz, 2H), 3.96 (s, 3H), 3.94 (t, J = 5.5 Hz, 2H), 3.76 (s, 3H), 2.52 - 2.45 (m, 2H). LC-MS method 2: m/z 367.2 [M+H] ⁺ , (ESI+), RT = 0.86.

Step 2: Methyl 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylate: 3 vacuum/nitrogen cycles with ethanol (2 mL) ) of methyl 2-(4-cyano-2-methoxy-phenoxy)-5-(3,6-dihydro-2H-pyran-4-yl)pyridine-3-carboxylate (100 mg, 0.273 mmol) was applied to the solution. Palladium (10%, 29 mg, 0.0273 mmol) was added and three vacuum/hydrogen cycles were applied. The mixture was stirred at room temperature for 4 hours. LC-MS analysis indicated that the starting material was consumed. Filtered through Celite and concentrated to give a clear oil. Purified by FCC (10 g, 0 to 100% EA in heptane) to give methyl 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridin-3-car Boxylate (87.0%) (28 mg, 0.0661 mmol, 24% yield) was obtained as a white semi-solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.17 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 2.5 Hz, 1H), 7.33 (dd, J = 8.2, 1.9 Hz, 1H), 7.25 - 7.18 (m, 2H), 4.15 - 4.04 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.52 (m, 2H), 2.79 (m, 1H), 1.81 - 1.73 (m) , 4H). LC-MS method 2: m/z 369.2 [M+H] ⁺ , (ESI+), RT = 0.83.

Step 3: 2-(4-Cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid: THF (0.2 mL) in water (0.1 mL) To a solution of methyl 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylate (28 mg, 0.0760 mmol), lithium hydroxide (4.2 mg, 0.167 mmol) was added and the mixture was stirred at room temperature for 2 hours. LC-MS analysis indicated that the reaction was complete. The mixture was diluted with water (5 mL) and the pH was adjusted to 1 by dropwise addition of 2M HCl (aq). The aqueous layer was extracted with EtOAc (3 x 5 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to give 2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran. -4-yl-pyridine-3-carboxylic acid (90.0%) (25 mg, 0.0635 mmol, 84% yield) was obtained as a clear oil. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 2.5 Hz, 1H), 7.46 - 7.32 (m, 2H), 4.10 (m, 2H) , 3.81 (s, 3H), 3.53 (m, 2H), 2.83 (m, 1H), 1.89 - 1.75 (m, 4H). LC-MS method 2: m/z 355.2 [M+H] ⁺ , (ESI+), RT = 0.69.

Step 4: 2-(4-Cyano-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-5-tetrahydropyran-4-yl-pyridine-3-carboxamide: Pyridine -2-(4-cyano-2-methoxy-phenoxy)-5-tetrahydropyran-4-yl-pyridine-3-carboxylic acid (25 mg, 0.0705 mmol) and 3 in anhydrous (0.4 mL) To a solution of -(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (16 mg, 0.0847 mmol) was added 3-(methylsulfanyl)aniline (12 mg, 0.0847 mmol). . The mixture was stirred at room temperature for 1 hour. LC-MS analysis indicated that the reaction was complete. The solvent was removed and the residue was purified by FCC (5 g, 0 to 60% EA in heptane) to give 2-(4-cyano-2-methoxy-phenoxy)-N-(3-methylsulfanyl Phenyl)-5-tetrahydropyran-4-yl-pyridin-3-carboxamide (87.0%) (17 mg, 0.0311 mmol, 44%) was obtained as an off-white solid. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, CDCl ₃ ) δ 9.92 (s, 1H), 8.51 (d, J = 2.5 Hz, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.98 - 7.92 (m, 2H) , 7.53 (m, 2H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.39 - 7.36 (m, 1H), 7.31 (d, J = 1.8 Hz, 1H), 4.10 (m, 2H), 3.89 (s, 3H), 3.60 - 3.49 (m, 2H), 2.91 - 2.81 (m, 1H), 2.76 (s, 3H), 1.89 - 1.79 (m, 4H). m/z 476.2 [M+H] ⁺ , (ESI+), RT = 1.01.

Step 5: 2-(4-Cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-5-tetrahydropyran-4-yl-pyridine-3-carbox Amide: Phenyl iodonium diacetate (PIDA) (35 mg, 0.107 mmol) and diammonium carbonate (10 mg, 0.107 mmol) were reacted with 2-(4-cyano-2-methoxy-phenocyl) in methanol (0.5 mL). si) -N- (3-methylsulfanylphenyl) -5-tetrahydropyran-4-yl-pyridine-3-carboxamide (17 mg, 0.0357 mmol) was added to the solution, and the reaction was incubated at room temperature for 2 hours. It was stirred for a while. LC-MS analysis indicated that the reaction was complete. The solvent was removed and the residue was purified by preparative HPLC (standard methods) to give 2-(4-cyano-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]- 5-Tetrahydropyran-4-yl-pyridine-3-carboxamide (98.0%) (10 mg, 0.0193 mmol, 54% yield) was obtained as a white solid after freeze-drying. ¹ H NMR and LC-MS analysis indicated that this was the desired product. ^1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.39 (m, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.94 (m, 1H), 7.70 - 7.66 (m, 1H), 7.64 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.8 Hz) , 1H), 7.45 (d, J = 8.2 Hz, 1H), 4.22 (s, 1H), 3.96 (m, 2H), 3.76 (s, 3H), 3.49 - 3.38 (m, 2H), 3.06 (s, 3H), 2.87 (m, 1H), 1.76 - 1.67 (m, 4H). LC-MS method 4: m/z 507.2 [M+H] ⁺ , (ESI+), RT = 2.53.

Example 100

Compound 1728: 5-Bromo-2-(4-fluoro-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-4 -Methylpyridine-3-carboxamide

Reagents & Conditions: a) K ₂ CO ₃ , DMF, 100°; b) K ₂ CO ₃ , H ₂ O ₂ (50%, v/v), DMSO; c) tert-butyl nitrite, AcOH, NaOH, 70°C; d) (S)-tert-Butyl N-[(3-aminophenyl)-methyl-oxo-λ ⁶ -sulfanylidene]carbamate. HATU, DIEA, DMF; e) 2-propanol, 4M HCl in dioxane, 1,4-dioxane

Step 1: 5-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carbonitrile

5-Bromo-2-chloro-4-methyl-pyridine-3-carbonitrile was prepared as described in WO2016021742A.

4-Fluoro-2-methyl-phenol (1.61 g, 12.8 mmol), 5-bromo-2-chloro-4-methyl-pyridine-3-carbonitrile (1.98 g, 8.53 mmol) in DMF-anhydrous (20 mL) mmol) and K ₂ CO ₃ (2.36 g, 17.1 mmol) was stirred at 100°C for 16 hours. The reaction was cooled to room temperature, poured into ice-cold water, and the mixture was extracted with EtOAc (25x3 mL). The combined layers were dried to give a crude residue. Purified by chromatography on silica eluting with a gradient of 0 to 20% EtOAc in heptane to give 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboni. Trill (100.0%) (1.00 g, 36%) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 7.29 - 7.18 (m, 2H), 7.16 - 7.05 (m, 1H), 2.60 (s, 3H), 2.09 (s, 3H) . m/z: 321.0 (Br isotope pattern) [M+H] ⁺ , (ESI+), RT = 4.21 LCMS method 4.

Step 2: 5-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboxamide

5-Bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carbonitrile (1.00 g, 3.11 mmol) was dissolved in DMSO (17.2 mL) and then Thiooxycarbonyloxypotassium (1.90 g, 13.7 mmol) was added. The reaction mixture was cooled slightly in a water bath. To the reaction mixture was added dropwise (slightly exothermic) 50% wt aqueous hydrogen peroxide (50%, 1.9 mL, 34.2 mmol) over 5 minutes, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (80 mL) and diluted HCl (1N) (25 mL). The organic phase was separated, washed with saturated NaHCO ₃ (2x25 mL) and brine (1x25 mL), dried and filtered. The solvent was removed under reduced pressure to yield 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboxamide (99.0%) (950 mg, 2.77 mmol, 89 %) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 8.08 - 8.07 (m, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 9.4, 3.0 Hz, 1H), 7.12 - 7.02 (m, 2H), 2.36 (s, 3H), 2.08 (s, 3H). m/z: 339.4 (Br isotope pattern) [M+H] ⁺ , (ESI+), RT = 2.85 LCMS method 4.

Step 3: 5-Bromo-2-(4-fluoro-2-methylphenoxy)-4-methylpyridine-3-carboxylic acid: 5-bromo-2-(4-) in acetic acid (1.5 mL) To a stirred solution of fluoro-2-methyl-phenoxy)-4-methyl-pyridine-3-carboxamide (170 mg, 0.501 mmol), tert-butyl nitrite (0.18 mL, 1.51 mmol) was added in N ₂ atmosphere. It was added slowly under pressure. The reaction mixture was then allowed to stir at 70°C for 2 hours. After completion, the reaction mixture was evaporated to dryness and NaOH (2 M) was added. The aqueous phase was washed with EtOAc (3 x 10 mL) and then the pH was adjusted to 1. The aqueous layer was then extracted with EtOAc (3 x 15 mL) and the organic layer was collected and dried to give 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine. -3-Carboxylic acid (89.0%) (154 mg, 0.403 mmol, 80%) was obtained as an orange solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.25 (s, 1H), 7.17 (dd, J = 9.5, 3.0 Hz, 1H), 7.10 (dd, J = 8.9, 5.2 Hz, 1H), 7.05 ( td, J = 8.5, 3.1 Hz, 1H), 2.38 (s, 3H), 2.05 (s, 3H). m/z: 340.0 (Br isotope pattern) [M+H] ⁺ , (ESI+), RT = 3.25 LCMS method 4.

Step 4: tert-Butyl N-[(S)-{3-[5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylpyridin-3-amido]phenyl}( methyl)oxo-λ ⁶ -sulfanylidene]carbamate; N-ethyl-N-(propan-2-yl)propan-2-amine (195 μL, 1.12 mmol), (S)-tert-butyl N-[(3-aminophenyl) in DMF-anhydrous (0.56 mL) -methyl-oxo-λ ⁶ -sulfanylidene]carbamate (83 mg, 0.307 mmol), 5-bromo-2-(4-fluoro-2-methyl-phenoxy)-4-methyl-pyridine- A mixture of 3-carboxylic acid (89%, 107 mg, 0.280 mmol) was stirred for 10 minutes. Next, HATU (160 mg, 0.421 mmol) was added. The reaction mixture was stirred at 55°C for 26 hours. The reaction mixture was concentrated under vacuum and then purified by flash chromatography. Fractions containing the target compound were combined and concentrated to give tert-butyl N-[(S)-{3-[5-bromo-2-(4-fluoro-2-methylphenoxy)-4-methylpyridine- 3-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (139 mg, 0.235 mmol, 84% yield) was obtained as a white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H), 8.46 - 8.37 (m, 1H), 8.32 (s, 1H), 7.98 - 7.90 (m, 1H), 7.70 - 7.65 (m) , 2H), 7.19 - 7.11 (m, 2H), 7.06 (td, J = 8.6, 3.1 Hz, 1H), 3.38 (s, 3H), 2.40 (s, 3H), 2.07 (s, 3H), 1.22 ( s, 9H). m/z: 492.0 (Br isotope pattern) [M-BOC+H] ⁺ , (ESI+), RT = 0.98 LCMS method 2.

Step 5: 5-Bromo-2-(4-fluoro-2-methylphenoxy)-N-{3-[(S)-imino(methyl)oxo-λ ⁶ -sulfanyl]phenyl}-4 -Methylpyridine-3-carboxamide. tert-Butyl N-[(S)-{3-[5-bromo-2-(4-fluoro-2-) in 1,4-dioxane-anhydride (1 mL) and 2-propanol (1 mL) To a solution of methylphenoxy)-4-methylpyridine-3-amido]phenyl}(methyl)oxo-λ ⁶ -sulfanylidene]carbamate (115 mg, 0.194 mmol) was added 4 M hydrogen chloride in 4 M dioxane ( 2.4 mL, 9.72 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then cooled to 0° C., diluted with ethyl acetate (20 mL), and the pH was adjusted to ˜9 using saturated NaHCO ₃ . Extracted with ethyl acetate (3 x 30 mL) and the organics were dried (MgSO ₄ ), filtered and concentrated. Purification by flash chromatography gave (100.0%) (31 mg, 33%) as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.41 - 8.39 (m, 1H), 8.31 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.68 ( d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 4.4 Hz, 1H), 7.14 (d, J = 4.5 Hz, 1H), 7.06 (td, J = 8.6, 3.0 Hz, 1H), 4.22 (s, 1H), 3.06 (s, 3H), 2.41 (s, 3H), 2.08 (s, 3H). m/z: 492.0 (Br isotope pattern) [M+H] ⁺ , (ESI+), RT = 2.98 LCMS method 4.

Example 101

Compound 1729: 2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-car Voxamide

Reagents & Conditions: a) 3-(methylthio)aniline, HATU, DIEA, DMF; b) bis(acetoxy)iodobenzene, (NH ₄ ) ₂ CO ₃ , MeOH; c) 3,4-difluoro-2-methoxy-phenol, K ₂ CO ₃ , acetonitrile, 70°C.

Step 1: 2-Chloro-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide

2-Chloro-6-(trifluoromethyl)pyridine-3-carboxylic acid (300 mg, 1.33 mmol), HATU (607 mg, 1.60 mmol) and DIPEA (465 uL, 2.66 mmol) in DMF (3.6 mL) 3-(methylthio)aniline (197 uL, 1.60 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 17 hours, then poured into water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with 5% aqueous LiCl (2 x 10 mL), dried over MgSO4 and concentrated under reduced pressure to give 737 mg as a brown gum. The crude product was purified by FCC (Biotage Isolera 4, 25 g Spa Duo, Lambda-all collection) using a 0-100% EtOAc/heptane gradient to give 2-chloro-N-(3-methylsulfanyl Phenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (97.0%) (277 mg, 58%) was obtained as a light yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.79 (br.s, 1H), 8.42 (d, J = 7.5 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 1.9 Hz, 1H), 7.42 (ddd, J = 8.1, 1.9, 0.9 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.05 (ddd, J = 7.8, 1.7, 0.9 Hz, 1H) ), 2.48 (s, 3H).

m/z: 347.0, 349.0 [M+H] ⁺ , (ESI+), RT = 0.93 LCMS method 2.

Step 2: 2-Chloro-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide: 2-chloro-N-( in methanol (11 mL) Bis(acetoxy)iodobenzene (574 mg, 1.78 mmol) in a solution of 3-methylsulfanylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (97%, 277 mg, 0.775 mmol) ) and ammonium carbonate (109 mg, 1.16 mmol) were added, and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then diluted with DCM, dry-loaded on silica and purified by column chromatography between 0-100% EtOAc in heptane followed by 0-20% MeOH in EtOAc (on a Biotage Spa Duo 10 g column, Lambda -All collections) purified using 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (95.0%) (272 mg , 88%) was obtained as a beige powder. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 8.45 (d, J = 7.5 Hz, 1H), 8.34 (t, J = 1.9 Hz, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.89 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.72 (dt, J = 7.8, 1.1 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 4.25 ( s, 1H), 3.07 (s, 3H). m/z: 378.1, 380.0 [M+H] ⁺ , (ESI+), RT = 0.68 LCMS method 2.

Step 3: 2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-car Boxamide: 2-chloro-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (120 mg, 0.318) in acetonitrile-anhydrous (2.4 mL) mmol), 3,4-difluoro-2-methoxy-phenol (56 mg, 0.349 mmol) and potassium carbonate (66 mg, 0.476 mmol) were stirred at 60°C for 17 hours. The reaction mixture was allowed to cool, diluted with MeCN (2 mL), filtered through a phase separator and the solid was washed with MeCN (2 x 2 mL). The combined filtrates were concentrated under reduced pressure to yield 183 mg as a yellow gum. The crude compound was purified by preparative HPLC (Purification Method 1). Product fractions were combined and concentrated under reduced pressure. The resulting residue was freeze-dried from MeCN-water (1:1) to give 2-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl. ]-6-(Trifluoromethyl)pyridine-3-carboxamide (99.0%) (129 mg, 80%) was obtained as a white powder. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.01 (s, 1H), 8.45 - 8.36 (m, 2H), 7.96 - 7.89 (m, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.69 (dt, J = 7.9, 1.2 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.32 - 7.18 (m, 2H), 4.24 (s, 1H), 3.81 - 3.73 (m, 3H) , 3.06 (s, 3H). m/z: 502.0 [M+H]+, (ESI+), RT = 3.40 LCMS method 4.

Compound 1730: (R)-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl )Nicotinamide

Reagents & Conditions: a) NaOEt in EtOH, 85°C; b) POCl ₃ , Et ³ N.HCl, 105°C; c) 4-hydroxy-3-methoxybenzonitrile, K ₂ CO ₃ , NMP, 100°C; d) LiOH, THF/H ₂ O; e) tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate, oxalyl chloride, DCM, DMF, DIEA; f) 4M HCl in dioxane, 1,4-dioxane, 2-propanol, room temperature.

Step 1: Ethyl 4-methyl-2-oxo-6-(trifluoromethyl)-1H-pyridine-3-carboxylate: ethyl malonate monoamide (1.56 g, 11.9 mmol) in ethanol (20 mL) and To a solution of (E)-1,1,1-trifluoro-4-methoxy-pent-3-en-2-one (2.00 g, 11.9 mmol) sodium ethoxide (21%, 23 mL, 61.8 mmol) was added and the mixture was heated at 85° C. for 17 hours. Aqueous 2M HCl was added to the reaction mixture at room temperature to pH 5 and volatiles were removed under reduced pressure. The remaining aqueous portion was extracted with EtOAc ( ₃ Romethyl)-1H-pyridine-3-carboxylate (86.0%) (1.49 g, 5.14 mmol, 43%) was obtained as a brown free-flowing oil. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 12.36 (br.s, 1H), 7.31 (s, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.28 ( t, J = 7.1 Hz, 3H). m/z: 250.1 [M+H] ⁺ , (ESI+), RT = 0.75 LCMS method 2

Step 2: Ethyl 2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate: Ethyl 4-methyl-2-oxo-6-(trifluoromethyl)-1H-pyridine- A mixture of 3-carboxylate (86%, 750 mg, 2.59 mmol), trimethylamine hydrochloride (1:1) (371 mg, 3.88 mmol) and phosphorus oxychloride (6.0 mL, 64.2 mmol) was pressurized at 105°C. -Stirred in relaxation vial for 17 hours. The reaction mixture was allowed to cool and then retreated with phosphorus oxychloride (2.0 mL, 21.4 mmol) and trimethylamine hydrochloride (1:1) (124 mg, 1.29 mmol). Heating at 105° C. was resumed for 18 hours. The reaction mixture was retreated again with phosphorus oxychloride (2.0 mL, 21.4 mmol) and trimethylamine hydrochloride (1:1) (124 mg, 1.29 mmol) at room temperature. Heating was resumed at 105°C for 18 hours. The cooled reaction mixture was added dropwise to a stirred solution of water and saturated aqueous Na ₂ CO ₃ (1:1, 50 mL). The mixture was neutralized by careful addition of solid Na ₂ CO ₃ and then the product was extracted with DCM (3 x 50 mL). The combined organic portions were dried using a phase separation cartridge and concentrated under reduced pressure to give ethyl 2-chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (87.0%) (425 mg, 1.38 mmol). , 53%) was obtained as a dark brown free-flowing oil. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (s, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H) .m/z: 268.0, 270.0 [M+H] ⁺ , (ESI+), RT = 0.97 LCMS Method 2.

Step 3: Ethyl 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate: Ethyl in NMP-anhydrous (2.5 mL) 2-Chloro-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (79%, 208 mg, 0.614 mmol), 4-hydroxy-3-methoxybenzonitrile (137 mg, 0.921 mmol) and potassium carbonate (255 mg, 1.84 mmol) were stirred in an Ace pressure tube at 100° C. for 22 hours. The reaction mixture was allowed to cool to room temperature and then diluted with DCM (15 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with DCM (2 x 15 mL). The combined organic portions were dried using a phase separator and concentrated under reduced pressure to give a brown free-flowing oil. The crude product was purified by FCC (Biotage Isolera, 10 g Spa Duo Cartridge, Lambda-All Collection) using a 0-25% EtOAc/heptane gradient. The product fractions were combined and concentrated under reduced pressure to yield ethyl 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (35.0%). (571 mg, 0.525 mmol, 86%) was obtained as a yellow free-flowing oil. 65% NMP w/w ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 - 7.67 (m, 2H), 7.50 (dd, J = 8.2, 1.8 Hz, 1H), 7.38 (d, J = 8.2 Hz) , 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 2.45 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). m/z: 381.1 [M+H] ⁺ , (ESI+), RT = 1.01 LCMS Method 2

Step 4: 2-(4-Cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid: THF (3 mL) - Water (1.5 mL) ) of ethyl 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylate (42%, 571 mg, 0.631 mmol) To the mixture, lithium hydroxide (45 mg, 1.89 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was retreated with lithium hydroxide (45 mg, 1.89 mmol) and stirring was continued for 5 hours at room temperature. Methanol (0.2 mL) was added to the reaction mixture and stirring was continued for 17 hours at room temperature. The reaction mixture was retreated with lithium hydroxide (45 mg, 1.89 mmol) and stirred for an additional 22 hours. The reaction mixture was diluted with water (15 mL), the pH was adjusted to 1 by dropwise addition of 2M HCl, then extracted with EtOAc (3 x 10 mL), dried using a phase separator and concentrated under vacuum to give 256 mg. was obtained as a light yellow gum. The crude product was purified by FCC (Biotage Isolera 4, 10 g Spa Duo, Lambda-all collection) using a 0-100% EtOAc/heptane gradient and flushed with 0-60% MeOH/EtOAc. Product fractions were combined and concentrated under reduced pressure to yield 2-(4-cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (99.0%) ( 108 mg, 0.304 mmol, 48%) was obtained as a white powder. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 7.68 (d, J = 1.8 Hz, 1H), 7.64 (s, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 3.73 (s, 3H), 2.45 (s, 3H). No acid protons observed at m/z: 353.1 [M+H] ⁺ , (ESI+), RT = 0.81 LCMS method 2.

Step 5: tert-Butyl (R)-((3-(2-(4-cyano-2-methoxyphenoxy)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)( methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate

2-(4-Cyano-2-methoxy-phenoxy)-4-methyl-6-(trifluoromethyl)pyridine-3-carboxylic acid (99%, 105 mg) in DCM-anhydrous (1.3 mL) , 0.295 mmol), dry DMF (4.6 uL, 0.0590 mmol) followed by oxalyl chloride (28 uL, 0.325 mmol) was added at room temperature under nitrogen. The reaction was stirred for 50 minutes. Subsequently tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (86%, 111 mg, 0.354) in DCM-anhydrous (0.5 mL) mmol) was added, followed by DIPEA (103 uL, 0.590 mmol) and the reaction was stirred at room temperature for 1 hour. Water (2 mL) was added to the reaction and the mixture was passed through a phase separator and rinsed with DCM (3 x 3 mL). The combined organic phases were concentrated under vacuum to yield 227 mg as a pale yellow foam. The crude product was purified by FCC on silica using 0-100% EtOAc in heptane, flushed with 0-20% MeOH in EtOAc (on a Biotage Spa Duo 10 g column) and concentrated in vacuo to give tert-butyl ( R)-((3-(2-(4-cyano-2-methoxyphenoxy)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ ⁶ -Sulfanylidene)carbamate (89.0%) (171 mg, 0.252 mmol, 85%) was obtained as an off-white solid. m/z: 505.1 [M-BOC+H] ⁺ , (ESI+), RT = 0.94 LCMS Method 2

Step 6: (R)-2-(4-cyano-2-methoxyphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl )Nicotinamide: tert-butyl (R)-((3-(2-(4-cyano-2-methoxyphenoc) in 1,4-dioxane-anhydrous (1.4 mL) and 2-propanol (1.4 mL) si)-4-methyl-6-(trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (89%, 168 mg, 0.247 mmol) 4 M HCl in dioxane (3.1 mL, 12.4 mmol) was added and the mixture was stirred at room temperature for 1 hour and 15 minutes. The reaction mixture was then cooled to 0° C., diluted with EtOAc (20 mL), and basified to pH 9 with saturated aqueous NaHCO ₃ . The layers were separated and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organic portions were dried over MgSO ₄ and concentrated to dryness in vacuo to give 206 mg crude material as a light yellow residue. The crude material was purified by acidic (0.1% formic acid) reverse phase chromatography (Spar C18 6g D Duo, 10-100% MeCN in water). The pure product fractions were concentrated under reduced pressure and the resulting residue was lyophilized from MeCN-water (1:1) to (R)-2-(4-cyano-2-methoxyphenoxy)-4-methyl- N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)nicotinamide (97.0%) (88 mg, 0.169 mmol, 68%) was obtained as a white powder. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 8.40 (t, J = 1.9 Hz, 1H), 7.88 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H), 7.72 ( s, 1H), 7.71 - 7.67 (m, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.9 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H) ), 4.22 (s, 1H), 3.75 (s, 3H), 3.09 - 3.04 (m, 3H), 2.48 (s, 3H). m/z: 505.1 [M+H] ⁺ , (ESI+), RT = 2.89 LCMS Method 4.

Compound 1731: (R)-5-Bromo-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)nicotinamide.

The title compound was prepared by a similar procedure described for compound 1728 using the appropriate starting materials. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 8.41 (t, J = 1.9 Hz, 1H), 8.31 (s, 1H), 7.91 - 7.84 (m, 1H), 7.75 - 7.66 (m, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.06 (td, J = 8.4, 3.1 Hz, 1H), 4.23 (s, 1H), 3.07 - 3.04 (m, 3H), 2.41 (s, 3H), 2.08 (s, 3H). m/z: 492.0 - 494.0 [M+H] ⁺ , (ESI+), RT = 2.98 LCMS Method 4.

Compound 1732: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-(piperidin-1-yl)- 6-(Trifluoromethyl)pyridazine-4-carboxamide.

The title compound was prepared by a similar procedure described for compound 1522 using the appropriate starting materials. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.24 (s, 1H), 8.31 (t, J = 1.9 Hz, 1H), 7.87 (ddd, J = 8.1, 2.2, 1.1 Hz, 1H), 7.72 ( dt, J = 8.0, 1.3 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.29 - 7.16 (m, 2H), 7.11 (td, J = 8.7, 3.3 Hz, 1H), 4.27 (d) , J = 1.3 Hz, 1H), 3.25 - 3.17 (m, 4H), 3.07 (d, J = 1.1 Hz, 3H), 2.12 (s, 3H), 1.64 - 1.43 (m, 6H). m/z: 552.1 [M+H] ⁺ , (ESI+), RT = 3.48 LCMS Method 4.

Compound 1733: (R)-3-(4-Cyano-2-methoxyphenoxy)-6-(6-methoxypyridin-3-yl)-5-methyl-N-(3-(S-methyl Sulfonimidoyl)phenyl)pyridazine-4-carboxamide

The title compound was prepared using the appropriate starting materials by a similar procedure described for compound 1531. ^1H NMR (400 MHz, MeOD) δ 6.92 (t, J = 2.0 Hz, 1H), 6.81 (m, 1H), 6.43 (m, 1H), 6.36 (dd, J = 8.6, 2.5 Hz, 1H), 6.29 (m, 1H), 6.11 (t, J = 8.0 Hz, 1H), 5.98 (d, J = 1.5 Hz, 1H), 5.93 - 5.85 (m, 2H), 5.42 (m, 1H), 2.45 (s) , 3H), 2.28 (s, 3H), 1.63 (s, 3H), 0.91 (s, 3H). m/z: 545.1 [M+H] ⁺ , (ESI+), RT = 2.46 LCMS Method 4.

Compound 1734: (R) N-[3-(N-acetyl-S-methyl-sulfonimidoyl)phenyl]-3-(4-cyano-2-methoxy-phenoxy)-5-methyl-6- (p-tolyl)pyridazine-4-carboxamide

The title compound was (R)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(p-tolyl) Prepared with pyridazine-4-carboxamide. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.38 (s, 1H), 8.43 - 8.39 (m, 1H), 7.95 (dt, J = 6.8, 2.1 Hz, 1H), 7.73 - 7.66 (m, 3H) ), 7.55 (dd, J = 8.2, 1.8 Hz, 1H), 7.52 - 7.43 (m, 3H), 7.36 (d, J = 7.9 Hz, 2H), 3.81 (s, 3H), 3.43 (s, 3H) , 2.40 (s, 3H), 2.35 (s, 3H), 1.98 (s, 3H). m/z: 570.1 [M+H] ⁺ , (ESI+), RT = 3.14 LCMS Method 4.

Compound 1735: (R)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(o-tolyl) Pyridazine-4-carboxamide.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.46 (t, J = 2.0 Hz, 1H), 7.98 (m, 1H), 7.83 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.49 - 7.31 (m, 5H), 7.24 (m, 1H), 3.83 (s, 3H), 3.17 (s, 3H), 2.21 (s, 3H), 2.13 (s, 3H). m/z: 528.2 [M+H] ⁺ , (ESI+), RT = 2.79 LCMS Method 4

Compound 1736: (R)-3-((6-cyano-2-methoxypyridin-3-yl)oxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6 -(Trifluoromethyl)pyridazine-4-carboxamide.

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 8.34 (t, J = 1.9 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.65 (d, J = 7.9 Hz, 1H), 4.27 (d, J = 1.2 Hz, 1H), 3.88 ( s, 3H), 3.08 (d, J = 1.1 Hz, 3H), 2.54 - 2.52 (m, 3H).

m/z: 507.3 [M+H] ⁺ , (ESI+), RT = 2.95 LCMS method 4.

Compound 1737: (R)-3-((6-cyano-2-methylpyridin-3-yl)oxy)-5-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)-6- (Trifluoromethyl)pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.39 (s, 1H), 8.35 (t, J = 1.9 Hz, 1H), 8.10 - 8.03 (m, 2H), 7.87 (ddd, J = 8.0, 2.2 , 1.1 Hz, 1H), 7.77 - 7.71 (m, 1H), 7.64 (t, J = 7.9 Hz, 1H), 4.27 (s, 1H), 3.11 - 3.02 (m, 3H), 2.57 - 2.54 (m, 3H), 2.41 (s, 3H). m/z: 491.4 [M+H] ⁺ , (ESI+), RT = 2.73 LCMS Method 4.

Compound 1738: (R)-3-(4-Cyano-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine- 4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 8.69 (s, 1H), 8.34 (t, J = 1.9 Hz, 1H), 7.93 (ddd, J = 8.0, 2.2, 1.1 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 1.0 Hz, 2H), 4.26 (s, 1H), 3.78 (s, 3H) ), 3.07 (s, 3H). m/z: 492.4 [M+H] ⁺ , (ESI+), RT = 2.84 LCMS method 4.

Compound 1739: (R)-3-(4-cyano-2-methoxyphenoxy)-5-methyl-N-(3-(S-methyl-N-(methylglycyl)sulfonimidoyl)phenyl) -6-(p-tolyl)pyridazine-4-carboxamide

^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (s, 1H), 8.44 (s, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.80 - 7.60 (m, 3H), 7.54 ( dd, J = 8.2, 1.7 Hz, 1H), 7.51 - 7.40 (m, 3H), 7.35 (d, J = 8.0 Hz, 2H), 3.80 (s, 3H),3.71-3.66 (m, 1H), 3.45 (s, 3H), 3.18 (s, 2H), 2.39 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H).

m/z: 599.1 [M+H] ⁺ , (ESI+), RT = 2.16 LCMS Method 2.

Compound 1740: (R)-5-(4-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl )Nicotinamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 8.46 (t, J = 2.0 Hz, 1H), 8.05 (s, 1H), 8.01 - 7.94 (m, 2H), 7.91 - 7.86 (m, 1H), 7.71 - 7.65 (m, 1H), 7.64 - 7.56 (m, 3H), 7.27 - 7.14 (m, 2H), 7.08 (td, J = 8.5, 3.1 Hz, 1H), 4.23 - 4.21 (m, 1H), 3.09 - 2.98 (m, 3H), 2.28 (s, 3H), 2.13 (s, 3H). m/z: 515.2 [M+H] ⁺ , (ESI+), RT = 3.06 LCMS Method 4.

Compound 1741: (S)-5-(4-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-methyl-N-(3-(S-methylsulfonimidoyl)phenyl )Nicotinamide

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 8.45 (t, J = 1.9 Hz, 1H), 8.05 (s, 1H), 7.99 - 7.94 (m, 2H), 7.91 - 7.87 (m, 1H), 7.70 - 7.66 (m, 1H), 7.64 - 7.57 (m, 3H), 7.22 - 7.14 (m, 2H), 7.07 (td, J = 8.6, 3.2 Hz, 1H), 4.23 - 4.21 (m, 1H), 3.12 - 3.02 (m, 3H), 2.28 (s, 3H), 2.12 (s, 3H). m/z: 515.2 [M+H] ⁺ , (ESI+), RT = 3.06 LCMS Method 4.

Compound 1742: N-(3-carbamoylphenyl)-4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic amides

Reagents & Conditions: a) EtOH, 90°C; b) 1-bromopyrrolidine-2,5-dione, α,α,α-trifluorotoluene, K ₂ CO ₃ , 70°C; c) 2,2,2-trichloroacetonitrile, triphenylphosphine, toluene, 100°C; d) 4-hydroxy-3-methoxybenzonitrile, K ₂ CO ₃ , acetonitrile, 60°C; e) LiOH, THF/H ₂ O; e) 3-Aminobenzamide, HATU, DIEA, DMF.

Step 1: Ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-5,6-dihydro-1H-pyrimidine-5-carboxylate: 2,2,2-trifluoroethane Midamide (0.40 mL, 4.46 mmol) and diethyl ethylidenepropanedioate (0.90 mL, 4.91 mmol) were dissolved in ethanol (5 mL) and heated in a pressure tube at 90°C for 2 hours. The mixture was concentrated and the residue was dissolved in water (10 mL). The pH was adjusted to pH 4 using 1M HCl and then extracted with ethyl acetate (3 x 10 mL). The organic portion was dried, filtered and concentrated to give a yellow oil. Purified by FCC (EtOAc in DCM) to give ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-5,6-dihydro-1H-pyrimidine-5-carboxylate (90.0%) ( 285 mg, 1.02 mmol, 21% yield) was obtained as a yellow oil. 1H-19F-NMR and LCMS analysis indicated that this was the desired product as an approximately 8:1 mixture of isomers. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 4.36 - 4.14 (m, 3H), 3.28 (d, J = 8.8 Hz, 1H), 1.39 (d, J = 6.9 Hz, 3H) , 1.29 (t, J = 7.1 Hz, 3H). m/z: 253.1 [M+H] ⁺ , (ESI+), RT = 0.63 LCMS method 2.

Step 2: Ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-1H-pyrimidine-5-carboxylate: α,α,α-trifluorotoluene (40 mL) in pressure vial. Of ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-5,6-dihydro-1H-pyrimidine-5-carboxylate (1.33 g, 5.29 mmol), 2,2'-( E)-diazene-1,2-diylbis(2-methylpropanenitrile) (0.043 g, 0.264 mmol), 1-bromopyrrolidine-2,5-dione (1.32 g, 7.41 mmol) and K ₂ CO A mixture of ₃ (7.31 g, 52.9 mmol) was heated at 70° C. for 1 hour. LCMS analysis indicated that the reaction was complete. The mixture was filtered through cotton wool, further eluted with MeCN and concentrated to give an orange oil. Purified by FCC (25 g, 0 to 100% EA in DCM then 0 to 15% MeOH in EA) to give ethyl 6-methyl-4-oxo-2-(trifluoromethyl)-1H-pyrimidine-5. -Carboxylate (91.0%) (0.60 g, 2.19 mmol, 41% yield) was obtained as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.49 (m, 2H), 2.78 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). m/z: 251.1 [M+H] ⁺ , (ESI+), RT = 0.68 LCMS method 2.

Step 3: Ethyl 4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate: Ethyl 6-methyl-4-oxo-2-(trifluoro) in anhydrous toluene (10 mL) To a solution of romethyl)-1H-pyrimidine-5-carboxylate (412 mg, 1.65 mmol) and triphenylphosphine (1296 mg, 4.94 mmol) was added 2,2,2-trichloroacetonitrile (0.25 mL, 2.47 mmol) was added. The mixture was heated at 100° C. for 0.5 hours. Filtered and concentrated to give ethyl 4-chloro-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (11.0%) (2402 mg, 0.984 mmol, 60% yield) as a brown oil. did. It was used directly in subsequent steps. m/z: 538.3 [2M+H] ⁺ , (ESI+), RT = 1.00 LCMS Method 2.

Step 4: Ethyl 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate: Ethyl in acetonitrile (10 mL) 4-Chloro-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (442 mg, 1.65 mmol) and 4-hydroxy-3-methoxybenzonitrile (295 mg, 1.97 mmol) K ₂ CO ₃ (455 mg, 3.29 mmol) was added to the solution. The mixture was stirred at 60°C for 3 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried (MgSO4), filtered and concentrated to give a brown oil. Purified by FCC (25 g, 0 to 100% EA in heptane) to give ethyl 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine- 5-Carboxylate (84.0%) (323 mg, 0.712 mmol, 43% yield) was obtained as a light yellow solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.24 (d, J = 1.9 Hz, 2H), 4.49 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 2.67 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H). m/z: 382.2 [M+H] ⁺ , (ESI+), RT = 1.04 LCMS Method 2.

Step 5: 4-(4-Cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid: THF (2.5 mL): Water (0.5 mL) solution of ethyl 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (323 mg, 0.847 mmol) To this, lithium hydroxide (47 mg, 1.86 mmol) was added and the mixture was stirred at 40° C. for 2 hours and then stirred at room temperature overnight. The mixture was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl (aq.). The aqueous layer was extracted with EtOAc (3 x 8 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to give a yellow oil. Purified by FCC (10 g, 0 to 20% MeOH in EA) to give 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5. -Carboxylic acid (323 mg, 0.847 mmol) was obtained as a light yellow foam. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.36 (dd, J = 8.2, 1.8 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.25 (m, 1H), 3.78 (s, 3H) , 2.79 (s, 3H). m/z: 354.2 [M+H]+, (ESI+), RT = 0.76 LCMS method 2

Step 6: N-(3-carbamoylphenyl)-4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxyx Amide: N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate ( 77 mg, 0.204 mmol) was dissolved in 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid in DMF-anhydrous (1.2 mL). To a solution of boxylic acid (60 mg, 0.170 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.059 mL, 0.340 mmol) was added. The mixture was stirred at room temperature for 5 minutes, then 3-aminobenzamide (98%, 31 mg, 0.221 mmol) was added. The mixture was stirred at room temperature for 1 hour. LCMS analysis indicated that the reaction was complete. The mixture was diluted with ethyl acetate (8 mL) and washed with water (3 x 4 mL) and brine (4 mL). The organic portion was dried (MgSO ₄ ), filtered and concentrated to give an orange oil. Purified by purification method 2, N-(3-carbamoylphenyl)-4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine- 5-Carboxamide (100.0%) (44 mg, 0.0933 mmol, 55% yield) was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (t, J = 1.9 Hz, 1H), 7.91 (m, 1H), 7.68 (m, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.46 - 7.39 (m, 2H), 3.81 (s, 3H), 2.69 (s, 3H). m/z: 472.5 [M+H] ⁺ , (ESI+), RT = 2.94 LCMS Method 4.

Compound 1743: 4-(4-Cyano-2-methoxy-phenoxy)-6-methyl-N-[3-(methylsulfonimidoyl)phenyl]-2-(trifluoromethyl)pyrimidine-5 -Carboxamide

The title compound was prepared using 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid and the appropriate substituted aniline. . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.45 (t, J = 2.0 Hz, 1H), 7.98 (m, 1H), 7.83 (m, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 7.47 - 7.37 (m, 2H), 3.81 (s, 3H), 3.17 (s, 3H), 2.69 (s, 3H). m/z: 506.5 [M+H] ⁺ , (ESI+), RT = 2.93 LCMS method 4.

Compound 1744: N-(4-carbamoylphenyl)-4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic amides

The title compound was prepared as described above using 4-(4-cyano-2-methoxy-phenoxy)-6-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylic acid and 4-aminobenzamide. Prepared using the coupling conditions described. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 7.95 - 7.87 (m, 3H), 7.78 - 7.71 (m, 3H), 7.56 (dd, J = 8.2, 1.8 Hz, 1H ), 7.50 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 3.78 (s, 3H), 2.63 (s, 3H). m/z: 472.2 [M+H] ⁺ , (ESI+), RT = 2.86 MET-uPLC-AB-101 (7 min, low pH).

Example 102

Compound Profiling for Na _V 1.8 - Human Na _V 1.8 Cell Line - SynchroPatch384PE Assay

Compounds were tested on recombinant human Na _V 1.8 stably transfected HEK cells using the SynchroPatch384PE system, an automated patch clamp device. Cells were cultured at 37°C/5% CO ₂ in DMEM medium supplemented with Glutamax I, 1% NEAA, and 10% FBS, and seeded in T175 flasks. After culturing the cells at 30°C for 1 day, sodium currents were recorded. On the day of recording, cells were detached with 0.05% trypsin-EDTA, resuspended in serum-free DMEM medium, placed in a SynchroPatch384PE 6°C pre-chilled cell hotel, and shaken at 200 rpm. Intracellular solution (IC) was 10, CsCl; 110, CsF; 20, EGTA; 10, contained HEPES at mM. Extracellular solution (EC) was 140, NaCl; 4, KCl; 5 glucose; 10, HEPES; 2, CaCl ₂ ; 1, contained MgCl ₂ in mM. Wash solutions were 40, NMDG; 100, NaCl; 4, KCl; 10, glucose; 10, HEPES; 5, CaCl ₂ ; 1, contained MgCl ₂ in mM.

Compounds were tested in triplicate in 0.1% DMSO and 0.03% pluronic acid. Compounds were diluted 1:3 in EC solution to generate a 10-point concentration response curve over a final concentration range of 20-0.001 μM in the assay plate. Each plate contained tetracaine and another instrumental compound as a positive control. Up to 8 compounds were tested on one plate. 250 μM tetracaine and 0.1% DMSO were used as high and low controls, respectively.

Whole-cell patch clamp recordings were performed according to Nanion's standard procedures for SynchroPatch384PE®. Cells were maintained at a holding potential of -120 mV. A depolarizing step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarizing step to -100 mV for 100 ms. Apply a 10 s inactivation step at -40 mV, followed by stepping to -100 mV for 20 ms, then stepping to 10 mV for 30 ms (P2 measurement), then returning to -100 mV for 30 ms. I ordered it. The sweep interval was 15 seconds with a sampling rate of 10 kHz. After establishment of whole-cell composition in EC, two washing steps with baseline buffer were performed to stabilize the baseline. Compounds were then applied to each well by SynchroPatch and currents were recorded in EC for 5 minutes before tetracaine was applied to achieve complete block at the end of the experiment. The potency of the compounds was assessed in two readouts, resting state block (P1 measurement) or inactivation state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) controls. IC50 values are listed in Table 16 below: “A” indicates an IC50 of up to 20 nM, “B” indicates an IC50 of greater than 20 nM and up to 40 nM, and “C” indicates an IC50 of greater than 40 nM and up to 200 nM. indicates IC50, and “D” indicates IC50 greater than 200 nM and less than or equal to 500 nM.

Table 16

ND- not determined

B. Examples of the Second Set of Compounds

Example 103

Compound 1: 2-(4-fluoro-2-methylphenoxy)-N-{3-[imino(( ² H ₃ )methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-(trifluoro Romethyl)pyridine-3-carboxamide

Reagents and conditions: LiOH.H ₂ O, THF/H2O, room temperature; b) 3-[ ₍ ^2H3 )methylsulfanyl]aniline, HATU, DIEA, DMF; c) PIDA, (NH ₄ ) ₂ CO ₃ , MeOH, rt.

Step 1: 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid: THF: methyl in water (33.4 mL; 5:1 v/v) In a solution of 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate (8.80 g, 26.1 mmol), LiOH.H ₂ O (5.61 g, 134 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 3 hours. At the end of this period, the solvent was evaporated and the residue was added with water (20 mL) and acidified with 1N HCl. The separated solid was filtered, washed with water (2x20 mL), and 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (7.6 g, 90 %) was obtained. ^1H NMR (300 MHz, CDCl ₃ ) δ 8.63 (dd, J = 2.6, 0.7 Hz, 1H), 8.47 (dq, J = 2.7, 0.9 Hz, 1H), 7.03 - 6.84 (m, 3H), 2.09 ( s, 3H).

Step 2: 2-(4-fluoro-2-methylphenoxy)-N-{3-[( ² H ₃ )methylsulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carbox Amide: 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylic acid (6.0 g, 19.0 mmol), 3-[( To a mixture of ^2H ₃ )methylsulfanyl]aniline (2.98 g, 20.9 mmol) was added HATU (10.9 g, 28.6 mmol) followed by DIEA (7.38 g, 57.1 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. At the end of this period water (30 mL) was added and extracted with EtOAc (2x40 mL). The EtOAc layer was washed with water (30 mL) and brine (30 mL), and the organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated. The crude material was chromatographed on SiO ₂ with a gradient of 0-30 EtOAc% in hexane to give 2-(4-fluoro-2-methylphenoxy)-N-{3-[( ^2H3 )methylsulfanyl]phenyl _. }-5-(trifluoromethyl)pyridine-3-carboxamide (7.80 g, 93%) was obtained. ^1H NMR (300 MHz, CDCl ₃ ) δ 9.63 (s, 1H), 8.92 - 8.87 (m, 1H), 8.41 (dq, J = 1.8, 0.9 Hz, 1H), 7.65 (t, J = 1.9 Hz, 1H), 7.29 - 7.16 (m, 2H), 7.09 - 6.92(m, 4H), 2.13 (s, 3H).

Step 3: 2-(4-fluoro-2-methylphenoxy)-N-{3-[imino(( ² H ₃ )methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-(trifluoro Romethyl)pyridine-3-carboxamide: 2-(4-fluoro-2-methylphenoxy)-N-{3-[( ^2H3 )methylsulfanyl]phenyl}- in MeOH (150 _mL ) To a solution of 5-(trifluoromethyl)pyridine-3-carboxamide (7.80 g, 17.7 mmol) was added ammonium carbonate (2.56 g, 26.6 mmol) and PIDA (13.1 g, 40.8 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours. At the end of this period, the solvent was evaporated and the crude material was dissolved in EtOAc (150 mL), washed with saturated NaHCO3 solution and the EtOAc layer was dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The crude mixture was chromatographed on SiO ₂ with a gradient of 0-10% MeOH in DCM to give 2-(4-fluoro-2-methylphenoxy)-N-{3-[imino(( ^2H3 )methyl) _. Oxo-λ ⁶ -sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide (6.02 g, 72%) was obtained. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 8.67 (dt, J = 2.5, 1.1 Hz, 1H), 8.61 - 8.52 (m, 1H), 8.39 (t, J = 1.9) Hz, 1H), 7.95 (dt, J = 8.2, 1.4 Hz, 1H),7.75 - 7.56 (m, 2H), 7.34 - 7.06 (m, 3H), 4.25 (s, 1H), 2.10 (s, 3H) .

Example 104

Compounds 2 and 3: (S)-2-(4-fluoro-2-methylphenoxy)-N-{3-[imino(( ² H ₃ )methyl)oxo-λ ⁶ -sulfanyl]phenyl} -5-(trifluoromethyl)pyridine-3-carboxamide and (R)-2-(4-fluoro-2-methylphenoxy)-N-{3-[imino(( ^2H3 ₎ methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide

2-(4-fluoro-2-methylphenoxy)-N-{3-[imino(( ² H ₃ )methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-(trifluoromethyl) A racemic mixture of pyridine-3-carboxamides was isolated using the following chiral purification method: mobile phase: 20% methanol: 80% CO ₂ ; Column: Chiralpak AD-H, 10 x 250 mm, 5 μm. Flow rate: 15ml/min. First eluting isomer (S)-2-(4-fluoro-2-methylphenoxy ₎ -N-{3-[imino(( ^2H3 )methyl)oxo-λ ⁶ -sulfanyl]phenyl}- 5-(trifluoromethyl)pyridine-3-carboxamide (S)-2-(4 _- fluoro-2-methylphenoxy)-N-{3-[imino(( ^2H3 )methyl) oxo-λ ⁶ -sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide. ^1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.66 (dd, J = 2.4, 1.0 Hz, 1H), 8.57 - 8.51 (m, 1H), 8.38 (t, J = 1.8 Hz) , 1H), 7.96 - 7.90 (m, 1H), 7.71 - 7.65 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.27 (dd, J = 8.9, 5.1 Hz, 1H), 7.20 ( dd, J = 9.5, 3.0 Hz, 1H), 7.11 (td, J = 8.5, 3.1 Hz, 1H), 4.21 (s, 1H), 2.09 (s, 3H). m/z 471.5 [M+H] ⁺ , (ESI+), RT = 4.04 LC-MS Method 5 and second eluting isomer (R)- 2-(4-fluoro-2-methylphenoxy)-N-{ 3-[imino(( ² H ₃ )methyl)oxo-λ ⁶ -sulfanyl]phenyl}-5-(trifluoromethyl)pyridine-3-carboxamide. ^1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.66 (dd, J = 2.4, 1.0 Hz, 1H), 8.57 - 8.51 (m, 1H), 8.38 (t, J = 1.9 Hz) , 1H), 7.98 - 7.90 (m, 1H), 7.72 - 7.67 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.27 (dd, J = 8.8, 5.1 Hz, 1H), 7.20 ( dd, J = 9.5, 3.0 Hz, 1H), 7.11 (td, J = 8.5, 3.0 Hz, 1H), 4.22 (s, 1H), 2.09 (s, 3H). m/z 471.5 [M+H] ⁺ , (ESI+), RT = 4.05 LC-MS Method 5.

Example 105

Compound profiling for Na _V 1.8 - Human Na _V 1.8 cell line - SynchroPatch384PE assay

Compounds were tested on recombinant human Na _V 1.8 stably transfected HEK cells using the SynchroPatch384PE system, an automated patch clamp device. Cells were cultured at 37°C/5% CO ₂ in DMEM medium supplemented with Glutamax I, 1% NEAA, and 10% FBS, and seeded in T175 flasks. After culturing the cells at 30°C for 1 day, sodium currents were recorded. On the day of recording, cells were detached with 0.05% trypsin-EDTA, resuspended in serum-free DMEM medium, placed in a SynchroPatch384PE 6°C pre-chilled cell hotel, and shaken at 200 rpm. Intracellular solution (IC) was 10, CsCl; 110, CsF; 20, EGTA; 10, contained HEPES at mM. Extracellular solution (EC) was 140, NaCl; 4, KCl; 5 glucose; 10, HEPES; 2, CaCl ₂ ; 1, contained MgCl ₂ in mM. Wash solutions were 40, NMDG; 100, NaCl; 4, KCl; 10, glucose; 10, HEPES; 5, CaCl ₂ ; 1, contained MgCl ₂ in mM.

Compounds were tested in triplicate in 0.1% DMSO and 0.03% pluronic acid. Compounds were diluted 1:3 in EC solution to generate a 10-point concentration response curve over a final concentration range of 20-0.001 μM in the assay plate. Each plate contained tetracaine and another instrumental compound as a positive control. Up to 8 compounds were tested on one plate. 250 μM tetracaine and 0.1% DMSO were used as high and low controls, respectively.

Whole-cell patch clamp recordings were performed according to Nanion's standard procedures for SynchroPatch384PE®. Cells were maintained at a holding potential of -120 mV. A depolarizing step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarizing step to -100 mV for 100 ms. Apply a 10 s inactivation step at -40 mV, followed by stepping to -100 mV for 20 ms, then stepping to 10 mV for 30 ms (P2 measurement), then returning to -100 mV for 30 ms. I ordered it. The sweep interval was 15 seconds with a sampling rate of 10 kHz. After establishment of whole-cell composition in EC, two washing steps with baseline buffer were performed to stabilize the baseline. Compounds were then applied to each well by SynchroPatch and currents were recorded in EC for 5 minutes before tetracaine was applied to achieve complete block at the end of the experiment. The potency of the compounds was assessed in two readouts, resting state block (P1 measurement) or inactivation state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) controls. IC50 values are listed in Table 17 below: “A” indicates an IC50 of up to 20 nM, “B” indicates an IC50 of greater than 20 nM and up to 40 nM, and “C” indicates an IC50 of greater than 40 nM and up to 200 nM. indicates IC50, and “D” indicates IC50 greater than 200 nM and less than or equal to 500 nM.

Table 17

C. Examples for the Third Set of Compounds

Example 106

Methods for preparing the compounds of the invention and the intermediates used in their synthesis are provided in the general synthetic schemes and specific synthetic procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise indicated. Alternatively, their preparation is easy and is known to those skilled in the art or is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “Dry” glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise indicated.

All reactions were performed under positive pressure of dry nitrogen or dry argon in flame-dried or oven-dried glassware and magnetically stirred unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise indicated. Yield was not optimized. Chemical names were generated using Chemdraw Professional 19.1 or Chemaxone available from PerkinElmer.

The reaction was monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD Millipore™. Purification was performed with a CombiFlash NextGen 300 automated flash chromatography system or using one of the preparative HPLC methods mentioned below.

Purification Method 1 (P1): Acidic Initial Method

Purification (METCR/Prep004) (P1) LC was performed using a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature) for 0.55 min in an injection volume of 1500 μL at a flow rate of 40 mL/min. A gradient of 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 10 - 95% B over 13.89 minutes and held for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 2 (P2): Acid Standard Method

Purification (METCR/Prep001) (P2) LC was performed using a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature) for 0.55 min in an injection volume of 1500 μL at a flow rate of 40 mL/min. A gradient of 30% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 30 - 95% B over 10.45 minutes and held for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.21 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 3 (P3): Basic Initial Method

Purification (METCR/Prep002) (P3) LC was performed using a Waters 10% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) followed by a gradient of 10 - 95% B over 13.89 minutes and held for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 4 (P4): Basic Standard Method

Purification (METCR/Prep003) (P4) LC was performed using a Waters A gradient of 30% B over 10.45 minutes (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) followed by a gradient of 30 - 95% B over 10.45 minutes and held for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.21 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

LCMC for analysis were collected using one of the following methods.

Method 1 (M1): Acid IPC Method (METCR1410 - MS17, MS18, MS19)

Analysis (MET/CR/1410) (M1) HPLC-MS was performed using a Kinetex Core Shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40°C) with 3 μL of A gradient of 5 - 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.1 min was performed in the injection volume over 1.2 min. A second gradient of 100 - 5% B was then applied over 0.01 minutes and held for 0.39 minutes. UV spectra were recorded at 215 nm using SPD-M20A PDA detector, spectral range: 210 - 400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 2 (M2):

Mass spectrometry data was collected using a Waters Acquiti H-Class ultra high pressure liquid chromatograph coupled to a Waters Acquity TQD mass spectrometer. Samples were separated and resolved using an Acquity UPLC BEH C18 column (2.1 x 50 mm). Compounds were eluted from the column using a 10-minute linear solvent gradient: 0-0.5 min, 5% B; 0.5 - 6.5 min, 100% B, 6.5-7.5 min; 100% B, 7.5-8.1 min; 5% B, 8.1-10 min; 5% B. Solvent flow rate is 0.45 mL per minute. Solvent A was water and solvent B was acetonitrile. Mass spectra were collected in positive or negative ion mode with the following parameters: 2.5 kV capillary voltage; 25 V sampling cone voltage; 140°C source temperature; 400°C desolvation temperature; Nitrogen desolvation at 800 L/hr.

Method 3 (M3): Basic IPC method (MET-uPLC-AB-2005 - MS16, MSQ5)

Analysis (MET/uPLC/AB2005) (M14) uHPLC-MS was performed using a Waters uPLC® BEHTM C18 column (2.1 mm x 30 mm, 1.7 μm; temperature 40°C), 1 μL injection at a flow rate of 1.0 mL/min. A gradient of 1 - 100% B in volume over 1.1 minutes (A = 2 mM ammonium bicarbonate in water, buffered to pH 10; B = acetonitrile) followed by 100% B over 0.25 minutes was performed. A second gradient of 100 - 1% B was then applied over 0.05 minutes and held for 0.4 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm. Mass spectra were obtained using a Waters Quatro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MathLynx and OpenLynx software.

Method 4 (M4): Acidic Final Analytical Method (METCR-uPLC-AB101 - MSQ1, MSQ2, MSQ4)

Analysis (MET/uPLC/AB101) (M4) uHPLC-MS was performed using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μm; temperature: 40°C) at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5.3 min (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.5 min was performed in an injection volume of 1 μL. A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm, and ELS data were collected on a Waters Acquity ELS detector when reported. Mass spectra were obtained using Waters SQD or Waters Acquity QDA. Data were integrated and reported using Waters MathLynx and OpenLynx software.

Method 5 (M5): Acidic Final Analytical Method (METCR1416 - MS18, MS19)

Analysis (MET/CR/1416) (M5) HPLC-MS was performed using a Waters Atlantis dC18 column (2.1 mm x 100 mm, 3 μm; temperature: 40°C) with an injection volume of 3 μL at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5 minutes (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.4 minutes was performed. A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.58 minutes. UV spectra were recorded at 215 nm using SPD-M20A PDA detector, spectral range: 210 - 400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 6 (M6): Basic Final Analysis Method (MET-uPLC-AB105 - MS16, MSQ5)

Analysis (MET/uHPLC/AB105) (M8) uHPLC-MS was performed using a Waters uPLC® BEHTM C18 column (2.1 mm x 100 mm, 1.7 μm column; temperature: 40°C) at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5.3 minutes (A = 2 mM ammonium bicarbonate in water, buffered to pH 10; B = acetonitrile) followed by 100% B over 0.5 minutes was performed at an injection volume of . A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm. Mass spectra were obtained using a Waters Quatro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MathLynx and OpenLynx software.

SFC chiral resolution was performed using the following method: Column: Daicel Chiralpak IG, 250 mm x 20 mm ID, 5 μm; Mobile phase A: CO ₂ / MeOH [0.2% NH ₃ (7M solution in MeOH)] = 70/30; Flow rate: 60 g/min; 214 nm. Temperature: 35℃

Unless otherwise stated, ¹ H nuclear magnetic resonance spectroscopy (NMR) spectra were obtained on a Bruker Avance III HD 500 MHz spectrometer, Bruker™ 300 MHz, or 500 MHz. , recorded on 400 MHz or 250 MHz. Chemical shifts δ are quoted in parts per million (ppm) relative to TMS and are calibrated using residual non-deuterated solvent as an internal reference. The following abbreviations are used to indicate multiplicity and general assignment: s (singlet), d (doublet), t (triple), q (quartet), dd (doublet of a doublet), ddd (doublet of a doublet) doublet), dt (doublet of triplets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triplet of doublets), qd (quartet of doublets) ), app. (obvious) and br. (broadness). The coupling constant J is rounded to the nearest 0.1 Hz.

Example 107

General synthesis reaction scheme

Several methods for preparing compounds of the invention are illustrated in the Schemes and Examples below. The invention further provides a process for the preparation of compounds of structural formula (I) as defined above. In some cases, the order in which the above schemes are performed can be varied to facilitate the reaction or avoid unwanted reaction products. The following examples are provided for illustrative purposes only and should not be construed as limiting the disclosed invention.

Scheme 1

Scheme 1 shows a general method for preparing the carboxamide derivatives of the present invention by treating carboxylic acid A-1 with R ₂ NH ₂ using the amide coupling agents HATU and DIEA as a base to obtain an intermediate of type A-2. indicates. Compounds of type A-3 can be obtained by reacting intermediates of type A-2 with various phenols in the presence of bases such as K ₂ CO ₃ , Cs ₂ CO ₃ , DIEA or Et ₃ N in organic solvents.

Scheme 2

Alternatively, compounds of formula A-3 can be prepared by starting from dichlorocarboxylic acid ester B-1 and reacting various substituted phenols in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH or other organic base. It can be synthesized in a five-step linear synthesis by nucleophilic substitution of Cl adjacent to the carboxylic acid ester to give the intermediate of type B-2. The intermediate of type B-2 was further treated with HI (50%), HI (57%) or HI (40%) to give the intermediate of type B-3. Variously substituted R ₃ groups can be introduced by Pd-mediated or Cu-mediated coupling with intermediates of type B-3 to give B4. Carboxylic acids of intermediate type B-5 can be prepared by hydrolyzing the ester intermediate of type B-4 using a base such as aqueous NaOH, KOH or LiOH. Alternatively, intermediate of type B-5 can be prepared by treating intermediate B-4 with aqueous 1-6N HCl. The carboxylic acid (B-5) is activated with acid chloride and coupled with R ₂ NH ₂ , or the carboxylic acid (B-5) is activated in an organic solvent and base such as DIEA, Et ₃ N, DMAP or pyridine. A-3 can be obtained by coupling with R ₂ NH ₂ using standard amide coupling reagents, including but not limited to HATU, TBTU, EDC or T ₃ P.

Scheme 3

Alternatively, compounds of formula A-3 can be prepared by reacting the Cl intermediate of type C-1 using various substituted phenols in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH or other organic base. It can be prepared by nucleolar substitution to give the intermediate of type C-2. Carboxylic acids of intermediate type C-3 can be prepared by hydrolyzing the ester intermediate of type C-2 using a base such as aqueous NaOH, KOH or LiOH. Alternatively, intermediate of type C-3 can also be prepared by treating intermediate C-2 with aqueous 1-6N HCl. The carboxylic acid (C-3) is activated with acid chloride and coupled with R ₂ NH ₂ , or the carboxylic acid (C-3) is activated in an organic solvent and base such as DIEA, Et ₃ N, DMAP or pyridine. A-3 can be obtained by coupling with R ₂ NH ₂ using standard amide coupling reagents, including but not limited to HATU, TBTU, EDC or T ₃ P.

Scheme 4

Alternatively, compounds of type A-3 can also be prepared by activating the carboxylic acid (A-1) with acid chloride and coupling with R ₂ NH ₂ , or by activating the carboxylic acid (A-1) with organic solvents and bases. D-1 can be obtained by coupling with R ₂ NH ₂ using standard amide coupling reagents, such as but not limited to TBTU, EDC or T ₃ P among DIEA, Et ₃ N, DMAP or pyridine. Compounds of type A-3 are obtained by treating intermediates of type D-1 with various phenols in the presence of bases such as NaH (60%), K ₂ CO ₃ , Cs ₂ CO ₃ , DIEA or Et ₃ N in organic solvents. It can be.

Example 108

specific synthesis

Intermediate 1: 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid

Reagents & Conditions: a) 4-fluoro-2-methylphenol, K ₂ CO ₃ , CH ₃ CN, 90°C, 16 hours; b) HI, 40°C, 5 hours; c) Methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, TBAI, CuI, DMF, 120° C., 2 hours; d) LiOH, THF, H ₂ O, room temperature.

Step 1: Methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate.

4-Fluoro-2-methyl-phenol (3.01 g, 23.8 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (4.70 g, 22.7 mmol) and potassium carbonate (47 mL) in acetonitrile (47 mL) The mixture (4.71 g, 34.1 mmol) was stirred at 80°C for 3 hours. The reaction was cooled to room temperature, filtered, and washed with MeCN (20 mL). The filtrate was concentrated under vacuum to give a crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 15% EtOAc in heptane gave methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (95.0 %) (4.10 g, 58%) was obtained as a light yellow oil. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (s, 1H), 7.29 - 7.20 (m, 2H), 7.16 - 7.06 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H) ). LC-MS (Method 5): m/z: 297/299 [M+H] ⁺ , (ESI+), RT = 4.26.

Step 2: Methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate:

Methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (4.10 g, 13.1 mmol) in hydroiodic acid (55%) (50 mL, 0.197 mol) ) The mixture was stirred at 40°C for 3 hours. The mixture was left at room temperature overnight. The reaction mixture was filtered. The filter cake was washed with water. The solid was redissolved in 55% aqueous hydrogen iodide (50 mL, 0.197 mol) and stirred at 40° C. for 24 hours. The mixture was cooled to room temperature, filtered, and the solid was washed with water and dried in a high vacuum oven at 40° C. overnight to obtain methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine- 4-Carboxylate (79.0%) (2.70 g, 5.50 mmol, 42% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.26 - 7.17 (m, 2H), 7.15 - 7.05 (m, 1H), 3.91 (s, 3H), 2.09 (s, 3H) ). LC-MS (Method 1): m/z: 388.9 [M+H]+, (ESI+), RT = 1.24.

Step 3: Methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: Methyl 3-(4-fluoro) in DMF (10 mL) Ro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (80%, 2.70 g, 5.57 mmol), copper iodide (1.598 g, 8.35 mmol), tetrabutylammonium i. Odide (0.824 g, 2.23 mmol) was added to the mixture. The mixture was degassed with nitrogen for 5 minutes, methyl difluoro(fluorosulfonyl)acetate (5.346 g, 27.8 mmol) was added, and stirred at 90°C for 2 hours. The reaction was cooled to room temperature, filtered, and the cake was washed with EtOAc (2 x 10 mL). The filtrate was washed with brine (50 mL), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 50% EtOAc in heptane gave the title compound methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine- 4-Carboxylate (0.770 g, 41%) as a light yellow solid, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 7.32 - 7.20 (m, 2H), 7.14 (td) , J = 8.5, 3.2 Hz, 1H), 3.97 (s, 3H), 2.13 (s, 3H). LC-MS (Method 1): m/z: 316.95 [M+H] ⁺ , (ESI+), RT = 1.06, and unreacted starting material methyl 6-chloro-3-(4-fluoro-2-methyl- Phenoxy)pyridazine-4-carboxylate (0.220 g, 13%) was obtained as a light yellow oil.

Step 4: 3-(4-Fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid: THF:H ₂ O (10 mL, 4:1; v /v) in a mixture of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (0.770 g, 2.31 mmol), lithium hydroxide (0.288 g, 11.5 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The solid was filtered, washed with water (2 x 10 mL), dissolved in EtOAc (20 mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound 3-(4-fluoro-2-methyl-phenoxy). )-6-(Trifluoromethyl)pyridazine-4-carboxylic acid (0.640 g, 87%) was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 7.31 - 7.22 (m, 2H), 7.18 - 7.09 (m, 1H), 2.12 (s, 3H). LC-MS (Method 1): m/z: 316.95 [M+H] ⁺ , (ESI+), RT = 1.06.

The intermediates listed in Table 18 were synthesized by a method similar to that described in Step 1 of Intermediate 1 synthesis using appropriate starting materials.

Table 18.

The intermediates listed in Table 19 were synthesized by a method similar to that described in step 2 of the synthesis of Intermediate 1 using the appropriate starting materials.

Table 19.

The intermediates listed in Table 20 were synthesized by a method similar to that described in step 3 of the synthesis of Intermediate 1 using the appropriate starting materials.

Table 20.

The intermediates listed in Table 21 were synthesized by a method similar to that described in step 4 of the synthesis of Intermediate 1 using the appropriate starting materials.

Table 21

Example 109

Intermediate 70: 2-Ethoxy-4-fluoro-phenol

(2-Ethoxy-4-fluoro-phenyl)boronic acid (0.725 g, 3.94 mmol) was dissolved in THF (15.7 mL) and cooled to 0°C. Then, 14.7 M hydrogen peroxide (50% aqueous solution) (50%, 1.2 mL, 17.3 mmol) and 2 M sodium hydroxide (3.9 mL, 7.88 mmol) were added. The reaction mixture was slowly warmed to room temperature. Stirred at room temperature for 90 minutes. The reaction was diluted with HCl (2N, 20mL) and water (10mL) and extracted with EtOAc (x2). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to a dark brown gum. Purification by column chromatography with a gradient of (0-50%) ethyl acetate and heptane gave the title compound 2-ethoxy-4-fluoro-phenol (0.503 g, 69%) as a light brown oil. ^1H NMR (400 MHz, CDCl ₃ ) δ 6.83 (dd, J = 8.7, 5.5 Hz, 1H), 6.60 (dd, J = 9.8, 2.8 Hz, 1H), 6.55 (td, J = 8.6, 2.8 Hz, 1H), 5.38 (s, 1H), 4.09 (q, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H). LC-MS (Method 3): m/z: 155.1 [MH]-, (ESI-), RT = 0.61.

Intermediates 71 and 72

tert-butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate [Intermediate 71] and tert-butyl (R)-((3-aminophenyl) Synthesis of (methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate [Intermediate 72].

Reagents & Conditions: _NH4 (OAc), PhI(OAc)2, EtOH, room temperature, 16 hours; b) t-BuOK, (Boc) ₂ O, t-BuOH, reflux, 10 hours; c) Pd(OH) ² , H ₂ , MeOH, room temperature, 2 hours; d) SFC purification

Step 1: Imino(methyl)(3-nitrophenyl)-λ ⁶ -sulfanone.

1 part PhI(OAc) ₂ (31.2 g, 97 mmol) to a mixture of methyl(3-nitrophenyl)sulfan (8.2 g, 48.5 mmol) and ammonium acetate (5.6 g, 72.7 mmol) in EtOH (120 mL). Added. The reaction mixture was stirred at room temperature under atmosphere for 16 hours. The mixture was concentrated directly to give a residue, which was purified by silica gel chromatography column (PE:EA=5:1 to 1:3) to give imino(methyl)(3-nitrophenyl)-λ ⁶ -sulphenyl. Fanone was obtained as a white solid (7.0 g, 72%). MS (ESI+): m/z actual value 201.03 [M+H] ⁺ .

Step 2: tert-Butyl (methyl(3-nitrophenyl)(oxo)-λ ⁶ -sulfanylidene)carbamate.

To a solution of imino(methyl)(3-nitrophenyl)-l6-sulfanone (3.5 g, 17.5 mmol) in t-BuOH (200 mL) cooled in an ice-water bath was added t-BuOK (3.9 g, 35.0 mmol) under N ₂ protection. mmol) was added. Subsequently, (Boc) ₂ O (7.6 g, 35.0 mmol) was added slowly and the reaction mixture was refluxed for 10 hours. The reaction mixture was quenched with saturated NH ₄ Cl solution (200 mL) and extracted with EA (200 mL x 2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give a residue, which was purified by silica gel chromatography column (PE:EA=5:1 to 1:1) to give tert- Butyl (methyl(3-nitrophenyl)(oxo)-λ ⁶ -sulfanylidene)carbamate was obtained as a yellow solid (1.8 g, 34%). LC-MS(ESI+): m/z 301.09 [M+H] ⁺ .

Step 3: (3-aminophenyl)(imino)(methyl)-λ ⁶ -sulfanone.

Pd(OH) ₂ (300 mg) in a solution of tert-butyl (methyl(3-nitrophenyl)(oxo)-λ 6 -sulfanylidene)carbamate ( ^1.8 g, 6 mmol) in MeOH (30 mL). was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite and washed with MeOH (100 mL). The filtrate was concentrated to give a residue, which was redissolved in EA (30 mL) and the resulting solution was filtered again through Celite and washed with EA (100 mL). The filtrate was concentrated to give tert-butyl ((3-aminophenyl) (methyl) (oxo)-λ ⁶ -sulfanylidene) carbamate (1.4 g, 86%) as an off-white solid. MS (ESI+): m/z actual value 271.10 [M+H] ⁺ .

Step 4: SFC isolation.

Chiral separation of the racemic product by chiral HPLC Conditions: Column: Daicel Chiralpak IG, 250 mm x 20 mm ID, 5 μm; Mobile phase A: CO ₂ / MeOH [0.2% NH ₃ (7M solution in MeOH)] = 70/30; Flow rate: 60 g/min; 214 nm. Temperature: 35°C was used for separation. The first eluting isomer tert-butyl (S)-((3-aminophenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate [Intermediate 71]. ^1H NMR (DMSO-d ₆ ) δ7.26 (t, 1H), 7.08(s, 1H), 6.97(d, 1H), 6.83(d, 1H), 5.71(s, 2H), 3.28(s, 3H), 1.27 (s. 9H) and the second eluting isomer tert-butyl (R)-((3-aminophenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate [Intermediate 72]. ^1H NMR (DMSO-d ₆ ) δ7.26 (t, 1H), 7.08(s, 1H), 6.97(d, 1H), 6.83(d, 1H), 5.71(s, 2H), 3.28(s, 3H), 1.27(s. 9H).

Example 110

Compound 1: 3-(4-fluoro-2-methoxyphenoxy)-N-(2-(methylsulfonyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-car Voxamide.

Reagents & Conditions: 2-Methylsulfonylpyridin-4-amine, 50% solution of propylphosphonic anhydride in EtOAc, DIEA, DMAP, DCM, room temperature.

50% solution of propylphosphonic anhydride (0.098 g, 0.309 mmol) in EtOAc, 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.090 g, 0.257 mmol), N,N-dimethylpyridin-4-amine (6.3 mg, 0.0515 mmol) and N-ethyl-N-isopropyl-propan-2-amine (DIEA) (0.090 mL, 0.515 mmol) The mixture was dissolved in DCM (1.28 mL) under nitrogen at room temperature. After 15 minutes, 2-methylsulfonylpyridin-4-amine (0.053 g, 0.309 mmol) was added in 1 portion. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (10 mL) and brine (5 mL), extracted with DCM (3 x 10 mL), dried over Na ₂ SO ₄ and concentrated. Purification by method 2 gave the title compound 3-(4-fluoro-2-methoxy-phenoxy)-N-(2-methylsulfonyl-4-pyridyl)-6-(trifluoromethyl)pyridazine. -4-Carboxamide (0.087 g, 69%) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.67 (s, 1H), 8.74 (d, J = 5.4 Hz, 1H), 8.68 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H) , 7.91 (dd, J = 5.4, 2.0 Hz, 1H), 7.39 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5) , 2.9 Hz, 1H), 3.73 (s, 3H), 3.29 (s, 3H). LC-MS (Method 1): m/z: 487.3 [M+H] ⁺ , (ESI+), RT = 3.15.

The compounds listed in Table 22 were synthesized by methods similar to those described for Compound 1 using the appropriate acid and substituted aniline.

Table 22

Example 111

Compound 59: 3-(4-Fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide

Reagents & Conditions: Pyridazine-4-amine, HATU, DIEA, DMF, 25°C, 1 hour;

N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (0.216 g , 0.569 mmol) and 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.150 g, 0.474 mmol) at room temperature under nitrogen. was dissolved in DMF (1.9 mL) under Pyridazin-4-amine (0.054 g, 0.569 mmol) was then added in 1 portion, followed by N-ethyl-N-isopropyl-propan-2-amine (0.17 mL, 0.949 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with brine (20 mL), extracted using EtOAc (2 x 10 mL) and the organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude residue. Obtained. Purification using Method A by preparative HPLC gave the title compound 3-(4-fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridazine- 4-Carboxamide (0.139 g, 75%) was obtained as an off-white solid. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.53 (s, 1H), 9.42 - 9.32 (m, 1H), 9.22 - 9.12 (m, 1H), 8.70 (s, 1H), 8.05 (dd, J = 6.0, 2.7 Hz, 1H), 7.35 (dd, J = 9.0, 5.0 Hz, 1H), 7.26 (dd, J = 9.4, 3.0 Hz, 1H), 7.16 (td, J = 8.6, 3.2 Hz, 1H) , 2.13 (s, 3H). LC-MS (Method 4): m/z 394.2 [M+H] ⁺ ,(ESI+), RT = 2.93

Compound 60: 3-(3-(2,4-difluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide.

Reagents & Conditions: 3-Aminopyridine 1-oxide, HATU, DIEA, DMF, 25°C, 16 hours;

3-(2,4-difluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.110 g, 0.34 mmol, 1.0 eq), 3-amino in DMF (10 mL) To a solution of pyridine 1-oxide (0.075 g, 0.68 mmol, 2.0 eq) and DIEA (0.222 g, 1.72 mmol, 5.0 eq) was added HATU (0.196 g, 0.52 mmol, 1.5 eq). The reaction mixture was stirred at 25°C for 16 hours. After reaction, the mixture was quenched with H ₂ O (40 mL), extracted with EtOAc (3x50 mL), the organic layer was concentrated and the residue was purified by preparative HPLC to give 3-(3-(2,4 -Difluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine-1-oxide (0.0405 g, 28%) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 8.73 (d, J = 4.2 Hz, 2H), 8.09 (d, J = 6.2 Hz, 1H), 7.70-7.40 (m, 4H), 7.25 (t, J = 8.5 Hz, 1H). MS(ESI+): m/z 413.1[M+H] ⁺ .

Compounds 61-88 listed in Table 23 were synthesized using methods similar to those described for compound 60 using the appropriate carboxylic acid and substituted aryl or heteroaryl aniline.

Table 23

Example 112

Compound 89: 3-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide

Reagents & Conditions: a) Iodotrimethylsilane, CH ₃ CN, 60°C, 24 hours

3-(2-chloro-4-fluorophenoxy)-N-(2-methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine-4- in anhydrous acetonitrile (10 mL) To a solution of carboxamide (0.117 g, 0.264 mmol) was added iodotrimethylsilane (0.062 mL) at room temperature. After complete addition of iodotrimethylsilane, the mixture was stirred at 60° C. for 24 hours. At the end of this period the mixture was cooled to room temperature, the solvent was evaporated to dryness, water (15 mL) was added and extracted with EtOAc (3x20 mL). The EtOAc layers were combined, washed with water (20 ml) and brine (20 mL), the organic layer was dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated. The mixture was chromatographed on SiO ₂ with a gradient of 0-15% EtOAc in DCM to obtain 3-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridine-4- 1)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.0416 g, 37%) was obtained. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.40 (s, 1H), 10.95 (s, 1H), 8.72 (s, 1H), 7.71 (dd, J = 8.4, 3.0 Hz, 1H),7.63 ( dd, J = 9.1, 5.2 Hz, 1H), 7.47 - 7.34 (m, 2H), 6.78 (d, J = 2.0 Hz, 1H), 6.38 (dd, J = 7.2, 2.1 Hz,1H). LC-MS (Method 2): m/z 427.0 [MH] ⁺ .

Compound 90: 3-(4-fluoro-2-methylphenoxy)-N-(5-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl) Pyridazine-4-carboxamide

The title compound was reacted with 3-(4-fluoro-2-methylphenoxy)-N-(2-methoxy-5-methylpyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-car It was prepared by a similar procedure described for compound 89 using boxamide. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 9.95 (s, 1H), 8.63 (s, 1H), 7.36 (dd, J = 8.9, 4.9 Hz, 1H), 7.27 ( dd, J = 9.5, 3.1 Hz, 1H), 7.24 (s, 1H), 7.17 (td, J = 8.6, 3.2 Hz, 1H), 7.11 (s, 1H), 2.15 (s, 3H), 2.00 (s) , 3H). LC-MS (Method 5): m/z 422.9 [M+H] ⁺ , (ESI+), RT = 3.83.

Compound 91: 3-(4-fluoro-2-methylphenoxy)-N-(3-methyl-2-oxo-1,2-dihydropyridin-4-yl)-6-(trifluoromethyl) Pyridazine-4-carboxamide

The title compound was reacted with 3-(4-fluoro-2-methylphenoxy)-N-(2-methoxy-3-methylpyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-car It was prepared by a similar procedure described for compound 89 using boxamide. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.47 (s, 1H), 10.26 (s, 1H), 8.63 (s, 1H), 7.35 (dd, J = 8.6, 5.3 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.16 (td, J = 8.6, 3.1 Hz, 1H), 6.76 (d, J = 7.1 Hz, 1H), 2.14 (s, 3H), 1.95 (s, 3H). LC-MS (Method 6): m/z 423.2 [M+H] ⁺ , (ESI+), RT = 3.05.

Compound 92: 3-(4-fluoro-2-methylphenoxy)-N-(2-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(trifluoromethyl) Pyridazine-4-carboxamide

The title compound was reacted with 3-(4-fluoro-2-methylphenoxy)-N-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic It was prepared by a similar procedure described for compound 89 using boxamide. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.73 (s, 1H), 10.10 (s, 1H), 8.61 (s, 1H), 7.43 (d, J = 9.5 Hz, 1H), 7.33 (dd, J = 9.0, 5.1 Hz, 1H), 7.26 (dd, J = 9.5, 3.0 Hz, 1H), 7.16 (td, J = 8.5, 3.2 Hz, 1H), 6.22 (d, J = 8.9 Hz, 1H), 2.16 (s, 3H), 2.14 (s, 3H). LC-MS (Method 6): m/z 423.2 [M+H] ⁺ , (ESI+), RT = 2.85.

Compound 93: 3-(4-fluoro-2-methyl-phenoxy)-6-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide

Reagents & Conditions: a) HATU, DCM, DIEA, room temperature, 18 hours; b) 4-fluoro-2-methyl-phenol, Cs ₂ CO ₃ , CH ₃ CN, room temperature, 16 hours; c) Diacetoxyiodo-benzene, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 3 hours.

Step 1: 6-Methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridin-3-yloxy)pyridazine-4-carboxamide. A mixture of 3-(methylsulfanyl)aniline (1.2 mL, 6.95 mmol) and 3-chloro-6-methylpyridazine-4-carboxylic acid (1.00 g, 5.79 mmol) was incubated with DCM (23.179) at room temperature under an atmosphere of nitrogen. mL). Then, N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate ( HATU) (2.42 g, 6.37 mmol) was added in 1 portion. N-ethyl-N-isopropyl-propan-2-amine (2.0 mL, 11.6 mmol) was added dropwise to the mixture over 2-3 minutes. The reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with saturated NaHCO ₃ solution (30 mL), stirred vigorously for 45 minutes and then extracted with DCM (30 mL x 2). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a dark brown crude residue. Purification by chromatography, eluting with a gradient of 0 to 50% EtOAc in heptane, gave the title compound 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridine-3. -yloxy)pyridazine-4-carboxamide (68.0%) (1.29 g, 2.23 mmol, 39% yield) was isolated as a beige solid. ^1H NMR (500 MHz, CDCl ₃ ) δ 9.51 (s, 1H), 8.72 (dd, J = 4.5, 1.4 Hz, 1H), 8.53 (dd, J = 8.4, 1.4 Hz, 1H), 8.10 (s, 1H), 7.71 (t, J = 1.9 Hz, 1H), 7.51 (dd, J = 8.4, 4.5 Hz, 1H), 7.46 (ddd, J = 8.1, 2.0, 0.8 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.10 (ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 2.76 (s, 3H), 2.51 (s, 3H). LC-MS (Method 3): m/z 394.4 [M+H] ⁺ , (ESI+), RT = 0.76.

Step 2: 3-(4-Fluoro-2-methyl-phenoxy)-6-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide. 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridin-3-yloxy)pyridazine-4-carboxamide (68%, 0.25 g, 0.432 mmol) and 4-fluoro-2-methyl-phenol (65 mg, 0.519 mmol) were suspended in anhydrous acetonitrile (4.3211 mL) under nitrogen atmosphere and treated with cesium carbonate (0.282 g, 0.864 mmol). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with saturated NH ₄ Cl solution (10 mL) and EtOAc (10 mL) and then stirred at room temperature for 10 minutes. The layers were shaken, separated and the aqueous portion was re-extracted with EtOAc (x1). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a brown gum. The material was purified by column chromatography using a gradient of EtOAc and heptane (0-100%) to give the title compound 3-(4-fluoro-2-methyl-phenoxy)-6-methyl-N-(3- Methylsulfanylphenyl)pyridazine-4-carboxamide (0.122 g, 71%) was obtained as a yellow/brown solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.75 (s, 1H), 8.21 (s, 1H), 7.71 (t, J = 1.8 Hz, 1H), 7.36 (m, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.17 (dd, J = 8.8, 4.8 Hz, 1H), 7.09 (dt, J = 7.7, 1.1 Hz, 2H), 7.05 (dd, J = 8.9, 2.9 Hz, 1H), 7.00 (td, J = 8.3, 3.1 Hz, 1H), 2.75 (s, 3H), 2.52 (s, 3H), 2.22 (s, 3H). LC-MS (Method 3): m/z 384 [M+H] ⁺ , (ESI+), RT = 0.89.

Step 3: 3-(4-Fluoro-2-methyl-phenoxy)-6-methyl-N-[3-(methylsulfonimidoyl)phenyl]pyridazine-4-carboxamide. 3-(4-Fluoro-2-methyl-phenoxy)-6-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (0.122 g, 0.318 mmol) was dissolved in methanol (3.2 mL). ) and treated with ammonium carbonate (0.046 g, 0.477 mmol) and diacetoxyiodo-benzene (0.236 g, 0.732 mmol) (each added in 1 part). After 60 minutes, additional ammonium carbonate (0.046 g, 0.477 mmol) and diacetoxyiodo-benzene (0.236 g, 0.732 mmol) were added. After a further 2 hours at room temperature, the mixture was concentrated under vacuum to give a brown gum. Purification using column chromatography with a gradient of methanol in ethyl acetate gave the impure title compound. This was further purified using preparative HPLC (Gilson 6) to obtain the title compound (0.064 mg, 47%). ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 8.36 (t, J = 1.9 Hz, 1H), 7.90 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 7.90 ( s, 1H), 7.70 (ddd, J = 7.8, 1.6, 1.1 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.25 (dd, J = 8.9, 5.1 Hz, 1H), 7.20 (dd , J = 9.4, 3.0 Hz, 1H), 7.11 (td, J = 8.5, 3.2 Hz, 1H), 4.24 (s, 1H), 3.07 - 3.05 (m, 3H), 2.61 (s, 3H), 2.10 ( s, 3H). LC-MS (Method 6): m/z 415.3 [M+H]+, (ESI+), RT = 2.55.

Compound 94: 3-(4-fluoro-2-methoxyphenoxy)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide

Reagents & Conditions: a) 4-fluoro-2-methoxyphenol, Cs ₂ CO ₃ , acetonitrile, room temperature, 16 hours; b) Diacetoxyiodo-benzene, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 3 hours.

Step 1—3-(4-fluoro-2-methoxyphenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide. 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridin-3-yloxy)pyridazine-4-carboxamide (68%, 0.500 g, 0.864 mmol) and 4-fluoro-2-methoxyphenol (0.150 g, 1.04 mmol) and cesium carbonate (0.563 g, 1.73 mmol) were suspended in anhydrous acetonitrile (8.6 mL) and the resulting mixture was incubated at room temperature for 16 hours. It was stirred for a while. The reaction was diluted with saturated NH ₄ Cl solution (20 mL) and DCM (10 mL) and then stirred at room temperature for 10 minutes. The layers were separated and the aqueous layer was re-extracted with DCM (10 mL). The combined organics were concentrated in vacuo to give a brown solid, which was purified by column chromatography (0-100%) using a gradient of ethyl acetate and heptane to give the title compound (0.320 g 88%) as a pink crystalline solid. did. ¹ H NMR (500 MHz, CDCl ₃ ): δ 9.84 (s, 1H), 8.18 (s, 1H), 7.71 (t, J = 1.9 Hz, 1H), 7.42 (dd, J = 8.6, 5.4 Hz, 1H ), 7.38 (ddd, J = 8.1, 2.0, 0.9 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.08 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 6.79 (dt, J = 4.6, 2.2 Hz, 1H), 6.78 - 6.74 (m, 1H), 3.79 (s, 3H), 2.78 (s, 3H), 2.52 (s, 3H). LC-MS (Method 6): m/z 400.5 [M+H] ⁺ , (ESI+), RT = 4.01.

Step 2- 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carbox amides. The title compound was reacted with 3-(4-fluoro-2-methoxyphenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide in step 3 of compound 93. It was prepared by a procedure similar to that described for. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 8.37 (t, J = 1.8 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.86 (s, 1H), 7.73 - 7.67 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.31 (dd, J = 8.8, 5.9 Hz, 1H), 7.10 (dd, J = 10.7, 2.9 Hz, 1H), 6.84 (td) , J = 8.5, 2.9 Hz, 1H), 4.24 (s, 1H), 3.70 (s, 3H), 3.06 (s, 3H), 2.61 (s, 3H). LC-MS (Method 6): m/z 431.3 [M+H]+, (ESI+), RT = 2.43.

Compound 95: 3-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl)pyridazine-4-carboxamide

Reagents & Conditions: a) 4-fluoro-2-methoxyphenol, Cs ₂ CO ₃ , acetonitrile, room temperature, 16 hours; b) Diacetoxyiodo-benzene, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 3 hours.

Step 1—3-(2-Ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide. The title compound (0.388 g, 99%) was reacted with 2-ethoxy-4-fluoro-phenol and 6-methyl-N-(3-methylsulfanylphenyl)-3-(triazolo[4,5-b]pyridine. -3-yloxy)pyridazine-4-carboxamide was prepared as an off-white crystalline solid by a method similar to that described for step 2 of compound 93 except that pyridazine-4-carboxamide was used. ^1H NMR (500 MHz, CDCl ₃ ): δ 9.83 (s, 1H), 8.16 (s, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.39 (dd, J = 9.4, 5.7 Hz, 1H ), 7.37 - 7.34 (m, 1H), 7.29 (t, J = 7.9 Hz, 1H), 7.08 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 6.79 - 6.76 (m, 1H), 6.75 ( d, J = 2.3 Hz, 1H), 4.00 (q, J = 7.0 Hz, 2H), 2.77 (s, 3H), 2.51 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H). LC-MS (Method 1): m/z 414.3 [M+H] ⁺ , (ESI+), RT = 0.90.

Step 2 - 3-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(S-methylsulfonimidoyl)phenyl) pyridazine-4-carboxamide. The title compound was reacted with 3-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4-carboxamide in step 3 of compound 93. It was prepared by a procedure similar to that described for. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 8.37 (t, J = 1.8 Hz, 1H), 7.96 - 7.88 (m, 1H), 7.87 (s, 1H), 7.71- 7.68 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.8, 5.9 Hz, 1H), 7.06 (dd, J = 10.7, 2.9 Hz, 1H), 6.82 (td) , J = 8.5, 2.9 Hz, 1H), 4.24 (s, 1H), 3.97 (q, J = 7.0 Hz, 2H), 3.06 (s, 3H), 2.61 (s, 3H), 1.05 (t, J = 7.0 Hz, 3H). LC-MS (Method 6): m/z 445.3 [M+H] ⁺ , (ESI+), RT = 2.62.

Compound 96: 3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

Reagents & Conditions: a) 3-(methylthio)aniline, HATU, DMF, DIEA, room temperature, 18 hours; b) Diacetoxyiodo-benzene, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 3 hours.

Step 1: 3-(2-Chloro-4-fluorophenoxy)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide. 3-(2-Chloro-4-fluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.100 g, 0.297 mmol), 3-(methylsul) in DMF (3 mL) To a mixture of panyl)aniline (0.041 g, 0.356 mmol), HATU (0.226 g, 0.594 mmol) was added DIEA (0.129 mL, 0.743 mmol) at 25°C and stirring was continued for an additional 2 hours at 25°C. At the end of this period water (5 mL) was added and extracted with EtOAc (3x25 mL). The organic layers were combined and washed with 1M LiCl solution (20 mL) followed by brine (20 mL). The EtOAc layer was dried (Na ₂ SO ₄ ), filtered and the solvent was evaporated. The crude mixture was chromatographed on SiO ₂ with a gradient of 0-60% EtOAc in hexane to give 3-(2-chloro-4-fluorophenoxy)-N-[3-(methylsulfanyl)phenyl]-6-( Trifluoromethyl)pyridazine-4-carboxamide (0.086 g, 63.23%) was obtained. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 8.70 (s, 1H), 7.79 - 7.54 (m, 3H), 7.49 - 7.22 (m, 3H), 7.07 (ddd, J = 7.8, 1.9, 1.1 Hz, 1H), 2.48 (s, 3H). LC-MS (Method 2): m/z 456.3 [MH] ⁺ .

Step 2: 3-(2-Chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide . 3-(2-chloro-4-fluorophenoxy)-N-[3-(methylsulfanyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.133 g, 0.291 mmol) ) was dissolved in methanol (5.0 mL) and treated with ammonium carbonate (0.42 g, 0.436 mmol) and diacetoxyiodo-benzene (0.215 mg, 0.668 mmol), each added in 1 portion. The reaction mixture was stirred at room temperature for 3 hours. At the end of this period the reaction mixture was concentrated under vacuum and the crude mixture was chromatographed on SiO ₂ eluting with a gradient of 0-100% EtOAc in DCM to give 3-(2-chloro-4-fluorophenoxy)-N. -(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.098 g, 69%) was obtained. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 8.73 (s, 1H), 8.35 (t, J = 1.9 Hz, 1H), 7.99 - 7.87 (m, 1H), 7.79 - 7.58 (m, 4H), 7.41 (ddd, J = 9.1, 8.1, 3.0Hz, 1H), 4.27 (s, 1H), 3.07 (d, J = 1.1 Hz, 3H). LC-MS (Method 2): m/z 489.5 [M+H] ⁺ .

Compound 97: 3-(2-chloro-4-fluorophenoxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide

Reagents & Conditions: a) 2-(methylthio)pyridin-4-amine, HATU, DMF, DIEA, room temperature, 18 hours; b) Diacetoxyiodo-benzene, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 3 hours.

Step 1: 3-(2-Chloro-4-fluorophenoxy)-N-(2-(methylthio)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide . The title compound (0.0913 g, 45%) was purified from 3-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)pyridazine-4- by a similar procedure described for step 1 of compound 96. Prepared using carboxylic acid and 2-(methylthio)pyridin-4-amine. ^1H NMR (300 MHz, CDCl ₃ ) δ 9.49 (s, 1H), 8.66 (s, 1H), 8.42 (dd, J = 5.6, 0.7 Hz, 1H), 7.63 (dd, J = 2.1, 0.7 Hz, 1H), 7.47 (dd, J = 9.1, 4.9 Hz, 1H),7.36 (dd, J = 7.7, 2.9 Hz, 1H), 7.31 - 7.15 (m, 3H), 2.59 (s, 3H).

Step 2: 3-(2-Chloro-4-fluorophenoxy)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide. The title compound (0.0366 g, 42%) was prepared by a similar procedure described for step 2 of compound 96. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.62 (s, 1H), 8.77 (s, 1H), 8.69 (d, J = 5.4 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H) , 7.86 (dd, J = 5.4, 2.1 Hz, 1H), 7.76 - 7.58 (m, 2H), 7.41 (ddd, J = 9.1, 8.1, 3.0 Hz, 1H), 4.44 (s, 1H), 3.16 (d) , J = 1.1 Hz, 3H). LC-MS (Method 2): m/z 490.4 [M+H] ⁺ .

Compound 98: 3-(4-fluoro-2-methylphenoxy)-N-(4-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

The title compound 3-(4-fluoro-2-methylphenoxy)-N-(4-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide Step of Compound 96 using 3-(4-fluoro-2-methylphenoxy)-N-(4-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide Prepared by a similar procedure described for 2. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.21 (s, 1H), 8.67 (s, 1H), 7.99 - 7.85 (m, 4H), 7.35 (dd, J = 8.9, 5.1 Hz, 1H), 7.25 (dd, J = 9.4, 2.9 Hz, 1H), 7.15 (td, J = 8.6, 3.2 Hz, 1H), 4.17 (s, 1H), 3.08 - 3.00 (m, 3H), 2.13 (s, 3H) . LC-MS (Method 5): m/z 469.1 [M+H]+, (ESI+), RT = 3.80.

Compound 99: 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxyx amides

Reagents & Conditions: 3-(methylthio)aniline, propylphosphonic anhydride (50% in EtOAc), DMAP, DIEA, DCM, room temperature, 3 hours; b) Diacetoxyiodo-benzene, (NH ₄ ) ₂ CO ₃ , MeOH, room temperature, 3 hours.

Step 1: 3-(4-Fluoro-2-methoxyphenoxy)-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. The title compound was reacted against compound 1 using 3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 3-(methylthio)aniline. Prepared by similar procedures described. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H), 8.60 (s, 1H), 7.67 (t, J = 1.9 Hz, 1H), 7.49 - 7.40 (m, 1H), 7.40 - 7.28 (m, 2H), 7.15 (dd, J = 10.7, 2.8 Hz, 1H), 7.10 - 6.99 (m, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.73 (s, 3H) , 2.48 (s, 3H). LC-MS (Method 1) m/z 453.9 [M+H]+, (ESI+), RT = 4.87.

Step 2: 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carbox amides. The title compound was 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylthio)phenyl)-6-(trifluoromethyl) by a similar procedure described for step 2 of compound 93. ) Pyridazine-4-carboxamide, prepared using (NH ₄ ) ₂ CO ₃ and diacetoxyiodo-benzene, to produce 3-(4-fluoro-2-methoxyphenoxy)-N-(3 -(S-Methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was obtained as a racemic mixture. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 8.63 (s, 1H), 8.38 - 8.32 (m, 1H), 7.96 - 7.88 (m, 1H), 7.77 - 7.69 (m , 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 4.27 (s, 1H), 3.73 (s, 3H), 3.07 (s, 3H). LC-MS (Method 1): m/z 485.0 [M+H]+, (ESI+), RT = 3.84.

Compounds 100 & 101: first eluting isomer and second eluting isomer

The racemic mixture from compound 99 was purified by SFC to give the title compound: first eluting isomer (compound 100) - ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H), 8.63 ( s, 1H), 8.35 (t, J = 1.8 Hz, 1H), 7.95 - 7.90 (m, 1H), 7.72 (dt, J = 7.8, 1.1 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H) ), 7.38 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 4.26 (s, 1H) , 3.73 (s, 3H), 3.07 (s, 3H). LC-MS (Method 6): m/z 485.3 [M+H] ⁺ , (ESI+), RT = 3.09 and second eluting isomer (Compound 101) - ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 8.61 (s, 1H), 8.34 (t, J = 1.9 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.74 - 7.69 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.37 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 4.25 (s) , 1H), 3.73 (s, 3H), 3.06 (s, 3H). LC-MS (Method 1): m/z 484.9 [M+H] ⁺ , (ESI+), RT = 3.83.

Compound 102: (R)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide

Reagents & Conditions: a) tert-Butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate [Intermediate 72], HATU, DIEA, DMF, room temperature, 1 hours; b) 4M HCl in dioxane, DCM, room temperature, 2 hours.

Step 1: tert-Butyl (R)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl) (methyl)(oxo)- λ ⁶ -sulfanylidene) carbamate: 3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine- in DMF (5 mL) 4-Carboxylic acid (300 mg, 0.95 mmol), tert-butyl (R)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate [Intermediate 72] (255 mg, 0.94 mmol) and N,N-diisopropylethylamine (366 mg, 2.8 mmol) at 25°C under nitrogen gas. Benzotriazol-1-yl)uranium (719 mg, 1.8 mmol) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with ice water and extracted with EA. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the crude product. The residue was chromatographed on SiO2 with a gradient of 0-60% EtOAc in petroleum ether to give tert-butyl (R)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(tri Fluoromethyl) pyridazine-4-carboxamido) phenyl) (methyl) (oxo) -λ ⁶ -sulfanylidene) carbamate (510 mg, 94%) was obtained as a yellow oil. LC-MS: m/z 591.0 [M+23] ⁺ .

Step 2: (R)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide. tert-Butyl (R)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido in DCM (3 mL) ) Phenyl) (methyl) (oxo) - λ ⁶ -sulfanylidene) To a mixture of carbamate (0.510 g, 0.89 mmol) was added HCl/1,4-dioxane (4M, 3 mL) at 25°C. . The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to give the crude product. The residue was purified by reverse phase flash chromatography (eluting with 0-45% ACN/H ₂ O (0.1% NH ₃ )) to give (R)-3-(4-fluoro-2-methylphenoxy)- N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.300 g, 71%) was obtained as an off-white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 8.67 (s, 1H), 8.35 (t, J = 4 Hz, 1H), 7.98 - 7.87 (m, 1H), 7.73 ( dt, J = 8 Hz, 1.2 Hz, 1H), 7. 65 (t, J = 8 Hz), 7.35 (dd, J = 8 Hz, 4 Hz, 1H), 7.26 (dd, J = 8 Hz, 3.2 Hz, 1H), 7.16 (td, J = 8.4 Hz, 3.2 Hz, 1H), 4.27 (s, 1H), 3.11 - 3.02 (s, 3H), 2.13 (s, 3H). LC-MS (ESI): m/z 469.1 [M+1] ⁺ .

Compound 103: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide

Reagents & Conditions: a) tert-Butyl (S)-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate [Intermediate 71], HATU, DIEA, DMF, room temperature, 1 hours; b) 4M HCl in dioxane, DCM, room temperature, 2 hours.

Step 1: tert-Butyl (S)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl) (methyl)(oxo)-λ ⁶ -sulfanylidene) carbamate. 3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.350 g, 1.1 mmol), tert-butyl (S) in DMF (5 mL) )-((3-aminophenyl)(methyl)(oxo)-λ ⁶ -sulfanylidene)carbamate (0.298 g, 1.1 mmol) and N,N-diisopropylethylamine (0.428 g, 3.3 mmol) HATU (0.839 g, 2.2 mmol) was added to the mixture at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ and concentrated to give the crude product, which was purified by flash chromatography (eluting with EA/PE 0-60%) to give tert-butyl (S)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)phenyl)(methyl)(oxo) -λ ⁶ -sulfanylidene) carbamate (0.550 g, 87%) was obtained as a yellow oil. LC-MS: m/z actual value 591.0 [M+23] ⁺ .

Step 2: (S)-3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide. tert-Butyl (S)-((3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido in DCM (3 mL) ) Phenyl) (methyl) (oxo) -λ ⁶ -sulfanylidene) To a mixture of carbamate (0.550 g, 0.96 mmol) was added HCl/1,4-dioxane (4M, 3 mL) at 25°C. . The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to give the crude product. The residue was purified by reverse-phase flash chromatography (eluting with ACN/H ₂ O (0.1% NH ₃ ) 0-45%) to give (S)-3-(4-fluoro-2-methylphenoxy)-N-. (3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.305 g, 67%) was obtained as an off-white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.20 (s, 1H), 8.67 (s, 1H), 8.35 (t, J = 4 Hz, 1H), 7.98 - 7.87 (m, 1H), 7.73 ( dt, J = 8 Hz, 1.2 Hz, 1H), 7. 65 (t, J = 8 Hz), 7.35 (dd, J = 8 Hz, 4 Hz, 1H), 7.26 (dd, J = 8 Hz, 3.2 Hz, 1H), 7.16 (td, J = 8.4 Hz, 3.2 Hz, 1H), 4.27 (s, 1H), 3.11 - 3.02 (s, 3H), 2.13 (s, 3H). LC-MS: m/z actual value 469.1[M+1] ⁺ .

Compounds 104 and 105: 3-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridazine-4-carboxamide and 3-(4- Fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfinylphenyl)pyridazine-4-carboxamide

Reagents & Conditions: Oxone, MeOH, room temperature, 16 hours

3-(4-Fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfanylphenyl)pyridazine-4-carboxamide (0.130 g, 0.325) in methanol (3.25 mL) mmol) was treated with Oxone (0.109 g, 0.716 mmol). The resulting mixture was stirred at room temperature overnight. Additional Oxone (0.109 g, 0.716 mmol) was then added and the mixture was stirred at room temperature for a further 6 hours. The reaction mixture was diluted with DCM (25 mL) and saturated NaHCO3 solution (25 mL). The layers were separated and the aqueous layer was re-extracted with DCM (25 mL). The combined organic portions were concentrated under vacuum to a light yellow solid. The material was purified using preparative HPLC method 1 to give 3-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonylphenyl)pyridazine-4-carboxylic acid. Amide (0.087 g, 61%) as a white solid, ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.18 - 8.12 (m, 3H), 7.76 (dt, J = 7.7, 1.3 Hz , 1H), 7.66 - 7.57 (m, 1H), 7.47 (dd, J = 8.7, 5.6 Hz, 1H), 6.84 - 6.74 (m, 2H), 3.82 (s, 3H), 3.09 (s, 3H), 2.76 (s, 3H). LC-MS (Method 6): m/z 432.3 [M+H]+, (ESI+), RT=2.78 and second title compound 3-(4-fluoro-2-methoxy-phenoxy)-6- Methyl-N-(3-methylsulfinylphenyl)pyridazine-4-carboxamide (0.015 g, 10%) was obtained as an off-white solid, ^1H NMR (500 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H ), 8.13 (t, J = 1.7 Hz, 1H), 7.86 (s, 1H), 7.81 - 7.76 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.42 (m, 1H), 7.31 (dd, J = 8.8, 5.9 Hz, 1H), 7.09 (dd, J = 10.7, 2.9 Hz, 1H), 6.84 (td, J = 8.5, 2.9 Hz, 1H), 3.70 (s, 3H), 2.75 ( s, 3H), 2.60 (s, 3H). LC-MS (Method 1): m/z 416.0 [M+H]+, (ESI+), RT=3.45 was obtained.

Compound 106: 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carbox amides

Reagents & Conditions: a) 4-methyl-3-(methylthio)aniline, propylphosphonic anhydride (50% in EtOAc), DMAP, DIEA, DCM, room temperature, 3 hours; b) Oxone, MeOH, room temperature, 16 hours.

Step 1: 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide . The title compound was prepared using 3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 4-methyl-3-(methylthio)aniline. Prepared by a similar procedure described for 1. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 10.83 (s, 1H), 8.63 (s, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 8.1, 2.0 Hz, 1H), 7.34 (dd, J = 8.9, 5.0 Hz, 1H), 7.25 (dd, J = 9.5, 3.0 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.15 (td, J = 8.5, 3.2 Hz) , 1H), 2.46 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H). LC-MS (Method 1): m/z 451.9 [M+H]+, (ESI+), RT = 5.05.

Step 2: 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carbox amides. The title compound was purified from 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoro) by a similar procedure described for compounds 104 and 105. Prepared using romethyl)pyridazine-4-carboxamide and excess oxone. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.19 (s, 1H), 8.65 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.2, 2.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 9.0, 5.0 Hz, 1H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.15 (td, J = 8.5 , 3.1 Hz, 1H), 3.23 (s, 3H), 2.62 (s, 3H), 2.13 (s, 3H). LC-MS (Method 1): m/z 451.9 [M+H]+, (ESI+), RT = 5.05.

Compound 107: 3-(4-fluoro-2-methoxyphenoxy)-N-(4-methyl-3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-car Voxamide

Reagents & Conditions: Oxone, MeOH, room temperature, 16 hours

3-(4-fluoro-2-methoxyphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide -(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid and 4-methyl-3-(methylthio)aniline for compound 1 Prepared by similar procedures described and used in subsequent steps. The title compound was purified from 3-(4-fluoro-2-methoxyphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(tri It was prepared using fluoromethyl)pyridazine-4-carboxamide. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.14 (s, 1H), 8.62 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 7.91 (dd, J = 8.3, 2.3 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5 , 2.9 Hz, 1H), 3.73 (s, 3H), 3.23 (s, 3H), 2.62 (s, 3H). LC-MS (Method 1): m/z 500.1 [M+H]+, (ESI+), RT = 4.33.

Compound 108: 3-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(methylsulfonyl)phenyl)pyridazine-4-carboxamide

Reagents & Conditions: Oxone, MeOH, room temperature, 16 hours

The title compound was purified from 3-(2-ethoxy-4-fluorophenoxy)-6-methyl-N-(3-(methylthio)phenyl)pyridazine-4- by a similar procedure described for compounds 104 and 105. Prepared using carboxamide and excess oxone. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.04 (s, 1H), 8.38 (t, J = 1.7 Hz, 1H), 7.95 (dt, J = 7.7, 1.5 Hz, 1H), 7.88 (s, 1H), 7.71 (dt, J = 7.8, 1.4 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 8.8, 5.9 Hz, 1H), 7.06 (dd, J = 10.7 , 2.9 Hz, 1H), 6.82 (td, J = 8.5, 2.9 Hz, 1H), 3.97 (q, J = 7.0 Hz, 2H), 3.22 (s, 3H), 2.61 (s, 3H), 1.04 (t , J = 7.0 Hz, 3H). LC-MS (Method 6): m/z 446.3 [M+H] ⁺ , (ESI+), RT = 2.97.

Compound 109: 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide

The title compound was reacted with 3-(4-fluoro-2-methylphenoxy)-N-(4-methyl-3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. was prepared by a similar procedure described for step 3 of compound 93 using . ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 8.64 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 7.89 (dd, J = 8.2, 2.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.9, 5.0 Hz, 1H), 7.25 (dd, J = 9.5, 2.9 Hz, 1H), 7.15 (td, J = 8.5 , 3.2 Hz, 1H), 4.29 (s, 1H), 3.08 (s, 3H), 2.66 (s, 3H), 2.13 (s, 3H). LC-MS (Method 1): m/z: 482.9 [M+H]+, (ESI+), RT = 4.01.

Compounds 110-113 listed in Table 24 were synthesized using a method similar to that described in Step 1 of Compound 59 using carboxylic acids with the appropriate substituted aryl or heteroaryl aniline.

Table 24

Compounds 114-117 listed in Table 25 were synthesized using methods similar to those described in Step 3 for Compound 93 using the appropriate substituted compounds listed in Table 24.

Table 25

Example 113

Compound 118: 3-(2-chloro-5-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

Reagents & Conditions: EDC, pyridine, room temperature, 16 hours.

3-(2-Chloro-5-fluorophenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (0.100 g, 0.316 mmol) in pyridine (4 mL), 3-aminobenzene-1 A mixture of -sulfonamide (0.082 g, 0.481 mmol) and EDC (0.0667 g, 0.348 mmol) was stirred at room temperature for 16 hours. The solvent was evaporated and the crude material was chromatographed on SiO2 with a gradient of 0-100% EtOAc in hexane to give 3-(2-chloro-5-fluorophenoxy)-N-(3-sulfamoylphenyl)-6- (Trifluoromethyl)pyridazine-4-carboxamide (0.086 g, 55.41%) was obtained. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.18 (s, 1H), 8.76 (s, 1H), 8.30 (t, J = 1.5 Hz, 1H), 7.83 (dt, J = 6.4, 2.4 Hz, 1H), 7.74 (dd, J = 9.0, 5.7 Hz, 1H), 7.67 -7.55 (m, 3H), 7.46 (s, 2H), 7.33 (ddd, J = 9.0, 8.1, 3.0 Hz, 1H). LC-MS (Method 1): m/z 489.4 [MH] ⁺ .

Compounds 119-129 listed in Table 26 were synthesized using methods similar to those described for compound 118 using an aryl or heteroaryl aniline substituted with the appropriate carboxylic acid.

Table 26

Example 114

Compound 130: 3-(4-fluoro-2-hydroxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

Reagents and conditions: Trichloroborane (1.0M in DCM), tetrabutylammonium iodide, DCM, 0°C.

Trichloroborane (1.0M in DCM, 1.0 mL, 1.03 mmol), tetrabutylammonium iodide (42 mg, 0.113 mmol) and 3-(4-fluoro-2-methoxy-phenoxy)-N-( 3-Methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (50 mg, 0.103 mmol) was stirred in anhydrous DCM (0.515 mL) at 0° C. for 1 h and transferred to an ice-water bath. Cooled. The reaction mixture was then concentrated under vacuum to obtain a crude residue. It was purified by chromatography on silica, eluting with a gradient of EtOAc in heptane. Fractions containing product were combined and concentrated. Purification by chromatography on silica eluting with a gradient of 0 to 100% EtOAc in heptane gave the title compound (0.014 mg, 28%) as a white solid and repurified by preparative LC. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (bs, 1H), 10.42 (bs, 1H), 8.58 (s, 1H), 8.41 - 8.36 (m, 1H), 7.96 (dt, J = 7.6 , 1.7 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.30 (dd, J = 8.8, 6.0 Hz, 1H), 6.78 - 6.71 (m, 1H), 6.71 - 6.63 (m, 1H), 3.23 ( s, 3H). (LC-MS (Method 5): m/z 472.0 [M+H] ⁺ , (ESI+), RT = 3.94.

Compound 131: 3-(4-fluoro-2-hydroxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

Title compound 3-(4-fluoro-2-hydroxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.020g, 66% ) except starting from 3-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide was prepared as a white solid by a similar method described for compound 130. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.15 (bs, 1H), 10.32 (bs, 1H), 8.59 (s, 1H), 8.31 - 8.28 (m, 1H), 7.84 (dt, J = 6.6 , 2.2 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.43 (s, 2H), 7.30 (dd, J = 8.8, 5.9 Hz, 1H), 6.77 (dd, J = 10.2, 2.8 Hz, 1H) , 6.74 - 6.65 (m, 1H). LC-MS (Method 6): m/z: 473.1[M+H] ⁺ .

Compound 132: N-(3-methanesulfonylphenyl)-3-[2-methyl-4-(1,2-oxazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridazine- 4-carboxamide

Reagents and conditions: KF, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole, pd(dppf)Cl ₂ . DCM, DMF, 60℃.

A solution of KF (0.0164 g, 0.283 mmol) in H ₂ O (0.200 mL) was reacted with 3-(4-bromo-2-methylphenoxy)-N-(3-methanesulfonyl) in DMF (3 mL) at room temperature. Phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (0.050 g, 0.094 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxabo Rolan-2-yl)-1,2-oxazole (0.022 g, 0.113 mmol) was added to the solution. The mixture was degassed by bubbling nitrogen for 10 minutes, pd(dppf)Cl ₂ .DCM (0.008 g, 10 mol%) was added to the mixture, and the resulting mixture was heated at 60° C. for 3 hours. At the end of this period, it was cooled to room temperature, water (5 mL) was added and extracted with EtOAc (2x 20 mL). The combined organic portion was washed with water (20 mL) and 1M LiCl (20 mL). The EtOAc layer was dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The crude mixture was chromatographed on SiO2 with a gradient of 0-20% EtOAc in DCM to obtain N-(3-methanesulfonylphenyl)-3-[2-methyl-4-(1,2-oxazol-4-yl). Phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxamide (0.021 g, 44%) was obtained. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 9.48 (s, 1H), 9.20 (s, 1H), 8.70 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.01 - 7.89 (m, 1H), 7.81 - 7.61 (m, 4H),7.38 (d, J = 8.4 Hz, 1H), 3.25 (s, 3H), 2.18 (s, 3H). LC-MS (Method 2): m/z 517.3 [MH] ⁺ .

Compound 133: 3-[2-methyl-4-(1H-pyrazol-4-yl)phenoxy]-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4- Carboxamide

Reagents & Conditions: a)tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate, Pd ₂ (dba) ₃ , Xphos, 1,4-dioxane, H ₂ O, 40°C; b) LiOH, THF, H ₂ O, room temperature; c) (i)DMAP. DIEA, 3-(methylsulfonyl)aniline, 50% solution of propylphosphonic anhydride in EtOAc, DCM, room temperature; (ii) 4 M HCl in dioxane, room temperature.

Step 1: Methyl 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylate .

Methyl 3-(4-bromo-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate in 1,4-dioxane (2 mL) and water (0.2 mL) (100 mg, 0.256 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxyl A suspension of rate (75 mg, 0.256 mmol), Pd ₂ (dba) ₃ (12 mg, 0.0128 mmol) and Xphos (6.1 mg, 0.0128 mmol) was degassed with nitrogen and stirred at 40° C. for 18.5 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3x 20 mL). The organic phases were combined, passed through a phase separator and concentrated under vacuum. The compound was purified by column chromatography on silica using 0-100% EtOAc in heptane, flushing with 0-60% MeOH in DCM (on a Biotage Spa 10 g column), and the compound was purified using DCM on silica. dry-loaded onto) methyl 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4 -Carboxylate (75.0%) (46 mg, 28%) was obtained as a light yellow oil. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.75 (s, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.69 (dd, J = 8.3, 2.1 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 2.17 (s, 3H), 1.64 - 1.56 (m, 9H). LC-MS (Method 3): m/z 379.2 [M+H]+, (ESI+), RT = 1.03.

Step 2: 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylate, Lithium salt.

THF (0.6 mL): Methyl 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl) in water (0.1 mL) ) To a mixture of pyridazine-4-carboxylate (75%, 46 mg, 0.0721 mmol), lithium hydroxide (4.5 mg, 0.180 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated under vacuum to give 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine-4-carboxylic acid. Boxylate, lithium salt (85.0%) (40 mg, 0.0723 mmol, 100% yield) was obtained as a light yellow solid. LC-MS (Method 1): m/z 365.05 [M+H]+, (ESI+), RT = 0.97. This material was used without further purification in subsequent steps.

Step 3. 3-[4-(1-tert-butoxycarbonylpyrazol-4-yl)-2-methyl-phenoxy]-6-(trifluoromethyl)pyridazine- in DCM (0.6 mL) 4-carboxylate lithium salt (40 mg, 0.0850 mmol), N-ethyl-N-isopropyl-propan-2-amine (0.030 mL, 0.170 mmol) and N,N-dimethylpyridin-4-amine (2.1 mg , 0.0170 mmol), a 50% solution of propylphosphonic anhydride in EtOAc (50%, 0.061 mL, 0.102 mmol) was added dropwise at room temperature and stirred for 10 minutes. 3-(Methylsulfonyl)aniline (17 mg, 0.102 mmol) was subsequently added in 1 portion and stirred at room temperature for 1 hour. The reaction was dissolved in 50% solution of propylphosphonic anhydride (50%, 0.061 mL, 0.102 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.030 mL, 0.170 mmol) in EtOAc, followed by DMF (0.1 mL). It was reprocessed to facilitate dissolution. The reaction was stirred at room temperature for 16 hours. The reaction was retreated with a 50% solution of propylphosphonic anhydride in EtOAc (50%, 0.061 mL, 0.102 mmol) and stirred at room temperature for 2 hours. The reaction was mixed with N-ethyl-N-isopropyl-propan-2-amine (0.030 mL, 0.170 mmol), N,N-dimethylpyridin-4-amine (2.1 mg, 0.0170 mmol), and 50% propylphosphonic anhydride in EtOAc. It was retreated with the solution (50%, 0.061 mL, 0.102 mmol) and stirred at 45°C for 1 hour. The reaction was concentrated in vacuo, 4 M HCl in dioxane (1.0 mL, 4.00 mmol) was added and the reaction was stirred at room temperature for 18 hours. The reaction mixture was poured into water (10 mL), extracted with DCM (3x 20 mL) and the combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by Purification Method 1, concentrated in vacuo, and lyophilized overnight to give the title compound 3-[2-methyl-4-(1H-pyrazol-4-yl)phenoxy]-N-(3-methyl Sulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide (6.0 mg, 14%) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 12.92 (s, 1H), 11.27 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.06 (s, 2H), 7.93 ( d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 2H), 7.61 (d, J = 1.7 Hz, 1H), 7.53 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 ( d, J = 8.4 Hz, 1H), 3.22 (s, 3H), 2.15 (s, 3H). LC-MS (Method 6): m/z 518.3 [M+H] ⁺ , (ESI+), RT = 2.94.

Compound 134: 3-(4-fluoro-2-methyl-phenoxy)-N-([1,2,4]triazolo[4,3-a]pyridin-5-yl)-6-(trifluoro Romethyl)pyridazine-4-carboxamide

Reagents & Conditions: a) Ammonium hydroxide (25%), 65°C; b) BrettPhos Pd G3,5-bromo[1,2,4]triazolo[4,3-a]pyridine, 1,4-dioxane, cesium carbonate, 90°C.

Step 1.3-(4-Fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide

Methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (300 mg, in ammonium hydroxide (25%, 1.9 mL, 45.4 mmol) 0.908 mmol) of the suspension was stirred at 65°C for 10 minutes. The mixture was cooled to room temperature and the suspension was filtered, washed with water (5 mL x 2) and dried at 40° C. under high vacuum for 2 hours to give the crude product. Purification using purification method P3 gave the title compound (175 mg, 61%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 8.21 (d, J = 5.3 Hz, 2H), 7.31 (dd, J = 8.9, 5.1 Hz, 1H), 7.25 (dd, J = 9.4, 3.0 Hz, 1H), 7.15 (td, J = 8.6, 3.1 Hz, 1H), 2.12 (s, 3H). LC-MS (Method 6): m/z 316.1[M+H] ⁺ , (ESI+), RT =2.95.

Step 2. 3-(4-Fluoro-2-methyl-phenoxy)-N-([1,2,4]triazolo[4,3-a]pyridin-5-yl)-6-(trifluoro Romethyl)pyridazine-4-carboxamide: BrettPhos Pd G3 (29 mg, 0.0317 mmol), 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine- A mixture of 4-carboxamide (100 mg, 0.317 mmol) and 5-bromo[1,2,4]triazolo[4,3-a]pyridine (94 mg, 0.476 mmol) was dissolved in anhydrous 1,4-di. Dissolve in oxane (3 mL) at room temperature under nitrogen. The mixture was degassed with nitrogen for 5 minutes and then cesium carbonate (207 mg, 0.634 mmol) was added in 1 portion. The reaction mixture was stirred at 90°C for 16 hours. The solvent was removed under vacuum and the crude residue was purified using preparative LC method P1 to give the title compound (95.0%) (13 mg, 9.3%) as a yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.66 (s, 1H), 9.33 (s, 1H), 8.79 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.49 (dd, J = 9.1, 7.3 Hz, 1H), 7.38 (s, 1H), 7.27 (dd, J = 9.2, 2.8 Hz, 2H), 7.17 (td, J = 8.5, 3.0 Hz, 1H), 2.16 (s, 3H) ). LC-MS (Method 4): m/z 433.2 [M+H] ⁺ , (ESI+), RT = 2.89.

Compound 135: 3-(4-fluoro-2-methylphenoxy)-N-(tetrazolo[1,5-a]pyridin-7-yl)-6-(trifluoromethyl)pyridazine-4- Carboxamide

A mixture of BrettPhos Pd G3 (29 mg, 0.0317 mmol), (100 mg, 0.317 mmol) and 7-bromotetrazolo[1,5-a]pyridine (95 mg, 0.476 mmol) was purified in anhydrous 1, at room temperature under nitrogen. Dissolved in 4-dioxane (3 mL). Cesium carbonate (207 mg, 0.634 mmol) was then added in 1 portion and the suspension was degassed for 5 minutes. The reaction mixture was stirred at 70°C for 2 hours. The mixture was filtered through a Celite plug, washed with MeOH (5 mL) and the solvent was removed under vacuum. Purification by preparative LC (method P1) gave the desired product (63 mg) containing impurities. The material was subsequently repurified by purification method P3 to give the title compound (26 mg, 19%) as a light yellow solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.67 (s, 1H), 9.30 (d, J = 6.9 Hz, 1H), 8.73 (s, 1H), 8.61 - 8.53 (m, 1H), 7.45 ( dd, J = 7.4, 2.1 Hz, 1H), 7.36 (dd, J = 9.0, 5.0 Hz, 1H), 7.26 (dd, J = 9.3, 2.9 Hz, 1H), 7.16 (td, J = 8.5, 3.2 Hz) ,1H), 2.14 (s, 3H). LCMS (Method 5) m/z 434.1 [M+H]+, (ESI+), RT = 4.08.

Compound 136: 3-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyrazine-2-car Voxamide

Reagents & Conditions: a) Titanium tetrachloride, tert-butyl nitrite, DCM, 0°C; b) 3,4-difluoro-2-methoxy-phenol, K ₂ CO ₃ , acetonitrile, 60°C; c) CuI, TBAI, methyl difluoro(fluorosulfonyl)acetate, DMF, 70°C; d) LiOH, THF/H ₂ O, room temperature; e) HATU, DIEA, 3-(methylsulfanyl)aniline, DMF, room temperature; f) (NH ₄ ) ₂ CO ₃ , (diacetoxyiodo)benzene, MeOH, room temperature

Step 1: Methyl 3-chloro-6-iodo-pyrazine-2-carboxylate: Methyl 3-amino-6-iodopyrazine-2-carboxylate (100%) in DCM-anhydrous (1.5 mL) at 0°C. mg, 0.358 mmol), titanium tetrachloride (38 uL, 0.358 mmol) was added, the red solution was stirred for 5 minutes, and then tert-butyl nitrite (90%, 95 uL, 0.717 mmol) was added, The solution was allowed to warm to ambient temperature. After 30 minutes, titanium tetrachloride (38 uL, 0.358 mmol) was added and the mixture was stirred at ambient temperature for 1 hour and then analyzed by LCMS. Water (~5 mL) was carefully added and the solution was extracted with DCM (~3 x 5 mL). The organic portion was passed through a phase separator and the solvent was removed under vacuum to give methyl 3-chloro-6-iodo-pyrazine-2-carboxylate (90.0%) (103 mg, 0.311 mmol, 87% yield) as a light yellow oil. It was obtained as. The material was used as crude material in subsequent steps.

Step 2: Methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-iodo-pyrazine-2-carboxylate: 3,4- in acetonitrile-anhydrous (1.5 mL) Difluoro-2-methoxy-phenol (62 mg, 0.387 mmol), methyl 3-chloro-6-iodo-pyrazine-2-carboxylate (110 mg, 0.369 mmol) and K ₂ CO ₃ (76 mg , 0.553 mmol) was stirred at 60°C overnight. The reaction was filtered through a phase separator, washed with DCM (3x 10 mL), concentrated under vacuum and purified by FCC (10 g silica; 0-100% MTBE in heptane). Product fractions (single peak on trace) were evaporated under vacuum to yield methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-iodo-pyrazine-2-carboxylate (82.0%). (55 mg, 0.107 mmol, 29% yield) was obtained as a colorless oil.

¹ H NMR (400 MHz, CD ₃ OD) δ 8.53 (s, 1H), 7.10 - 6.97 (m, 2H), 4.00 (s, 3H), 3.85 - 3.83 (m, 3H) m/z: 423.0 [M +H] ⁺ , (ESI+), RT = 0.95 LCMS method 2.

Step 3: Methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylate: in DMF-anhydrous (0.5 mL) under N2 Methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-iodo-pyrazine-2-carboxylate (55 mg, 0.130 mmol), copper iodide (37 mg, 0.195 mmol) and N,N,N-tributylbutane-1-aminium iodide (TBAI) (19 mg, 0.0521 mmol) in a mixture of methyl difluoro(fluorosulfonyl)acetate (0.083 mL, 0.651 mmol) ) was added. The reaction mixture was heated to 70° C. and stirred at this temperature for 3.5 hours. The reaction mixture was cooled to room temperature, filtered, poured into water and extracted with EtOAc (3×). The combined organic phases were washed with brine (5×), dried over MgSO4, filtered and concentrated in vacuo to give methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(tri Fluoromethyl)pyrazine-2-carboxylate (90.0%) (36 mg, 0.0890 mmol, 68% yield) was obtained as a dark brown oily solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.59 (s, 1H), 6.99 - 6.95 (m, 3H), 3.94 (s, 3H), 3.78 - 3.74 (m, 3H). ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -68.23, -140.04 - -141.07 (m), -154.06 - -155.17 (m).

Step 4: 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylic acid: THF (0.3 mL): Water (0.1 mL) To a mixture of methyl 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylate (39 mg, 0.106 mmol), LiOH ( 21 mg, 0.848 mmol) was added and the mixture was stirred at room temperature for 38 hours. The reaction was diluted with water (40 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The aqueous layer was extracted with EtOAc (3x 40 mL), passed through a phase separator and concentrated under vacuum. The product was used in subsequent steps without further purification.

Step 5: 3-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyrazine-2-carboxamide: 3-(3,4-difluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyrazine-2-carboxylic acid (28 mg, 0.0800 mmol), N in DMF (0.1969 mL) A mixture of -ethyl-N-isopropyl-propan-2-amine (DIEA) (0.028 mL, 0.160 mmol), HATU (36 mg, 0.0959 mmol) and 3-(methylsulfanyl)aniline (13 mg, 0.0959 mmol) was stirred at room temperature for 1 hour. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (3x 30 mL). The combined organic phases were passed through a phase separator and concentrated under vacuum. The compound was purified by FCC on silica using 0-100% EtOAc in heptane (on a Biotage Spa 10 g column, the compound was wet-loaded using DCM) to give 3-(3,4-difluoro- 2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyrazine-2-carboxamide (55.0%) (68 mg, 0.0793 mmol, 99%) Obtained as a light yellow solid. m/z: 472.1 [M+H] ⁺ , (ESI+), RT = 1.07 LCMS Method 2

Step 6: 3-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyrazine-2-car Boxamide: 3-(3,4-difluoro-2-methoxy-phenoxy)-N-(3-methylsulfanylphenyl)-6-(trifluoromethyl)pyrazine- in methanol (1 mL) To a suspension of 2-carboxamide (60%, 68 mg, 0.0866 mmol), (diacetoxyiodo)benzene (64 mg, 0.199 mmol) and (NH ₄ ) ₂ CO ₃ (12 mg, 0.130 mmol) were added. After addition, the reaction was stirred at room temperature for 4 hours. The reaction was concentrated under vacuum and purified by Purification Method 1. Fractions were evaporated under vacuum to give 3-(3,4-difluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyrazine- 2-Carboxamide (99.0%) (10 mg, 0.0203 mmol, 23% yield) was obtained as an off-white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.75 (s, 1H), 8.54 (t, J = 1.9 Hz, 1H), 8.09 (dd, J = 8.1, 1.2 Hz, 1H), 7.89 - 7.82 (m , 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.18 - 7.05 (m, 2H), 3.90 (d, J = 1.7 Hz, 3H), 3.20 (s, 3H). m/z: 501.3 [MH]-amino, (ESI-), RT = 3.07 LCMS method 4.

Example 115

Compound profiling for NaV1.8 - Human NaV1.8 cell line - SynchroPatch384PE assay

Compounds were tested on recombinant human Nav1.8 stably transfected HEK cells using the SynchroPatch384PE system, an automated patch clamp device. Cells were cultured at 37°C/5% CO2 in DMEM medium supplemented with Glutamax I, 1% NEAA, and 10% FBS and seeded in T175 flasks. After culturing the cells at 30°C for 1 day, sodium currents were recorded. On the day of recording, cells were detached with 0.05% trypsin-EDTA, resuspended in serum-free DMEM medium, placed in a SynchroPatch384PE 6°C pre-chilled cell hotel, and shaken at 200 rpm. Intracellular solution (IC) was 10, CsCl; 110, CsF; 20, EGTA; 10, contained HEPES at mM. Extracellular solution (EC) was 140, NaCl; 4, KCl; 5 glucose; 10, HEPES; 2, CaCl ₂ ; 1, contained MgCl ₂ in mM. Wash solutions were 40, NMDG; 100, NaCl; 4, KCl; 10, glucose; 10, HEPES; 5, CaCl ₂ ; 1, contained MgCl ₂ in mM.

Compounds were tested in quadruplicate in 0.1% DMSO and 0.03% pluronic acid. Compounds were diluted 1:3.33 in EC solution to generate a 10-point concentration response curve over a final concentration range of 10-0.0002 μM in the assay plate. Compounds with low nM potency were retested using a lower concentration range (1-0.00002 μM). Each plate contained tetracaine and another instrumental compound as a positive control. Up to 7 compounds were tested on one plate. 150 μM tetracaine and 0.1% DMSO were used as high and low controls, respectively.

Whole-cell patch clamp recordings were performed according to Nanion's standard procedures for SynchroPatch384PE®. Cells were maintained at a holding potential of -120 mV. A depolarizing step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarizing step to -100 mV for 100 ms. Apply a 10 s inactivation step at -40 mV, followed by stepping to -100 mV for 20 ms, then stepping to 10 mV for 30 ms (P2 measurement), then returning to -100 mV for 30 ms. I ordered it. The sweep interval was 15 seconds with a sampling rate of 10 kHz. After establishment of whole-cell composition in EC, two washing steps with baseline buffer were performed to stabilize the baseline. Compounds were then applied to each well by SynchroPatch and currents were recorded in EC for 5 minutes before tetracaine was applied to achieve complete block at the end of the experiment. The potency of the compounds was assessed in two readouts, resting state block (P1 measurement) or inactivation state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) controls.

Table 27 presents the potency of compounds against human NaV1.8, where “A” represents an IC50 of 200 nM or less, “B” represents an IC50 of greater than 201 nM and less than or equal to 500 nM, and “C” represents an IC50 of 501 nM or less. Indicates an IC50 greater than nM and up to 1000 nM, “D” indicates an IC50 greater than 1001 nM and up to 5000 nM, and “E” indicates an IC50 greater than 5001 nM.

Table 27

D. Examples for the Fourth Set of Compounds

Example 116

Methods for preparing the compounds of the invention and the intermediates used in their synthesis are provided in the general synthetic schemes and specific synthetic procedures below. Chemicals were purchased from standard commercial vendors and used as received unless otherwise indicated. Alternatively, their preparation is easy and is known to those skilled in the art or is referenced or described herein. Abbreviations are consistent with those in the ACS Style Guide. “Dry” glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise indicated.

All reactions were performed under positive pressure of dry nitrogen or dry argon in flame-dried or oven-dried glassware and magnetically stirred unless otherwise indicated. Chemicals were purchased from standard commercial vendors and used as received unless otherwise indicated. Yield was not optimized. Chemical names were generated using Chemdraw Professional 19.1 or Chemaxone available from PerkinElmer.

The reaction was monitored by thin layer chromatography (TLC) using 0.25 mm silica gel 60 F254 plates purchased from EMD Millipore™. Purification was performed with a CombiFlash NextGen 300 automated flash chromatography system or using one of the preparative HPLC methods mentioned below.

Purification Method 1 (P1): Acidic Initial Method

Purification (METCR/Prep004) (P1) LC was performed using a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature) for 0.55 min in an injection volume of 1500 μL at a flow rate of 40 mL/min. A gradient of 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 10 - 95% B over 13.89 minutes and held for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 2 (P2): Acid Standard Method

Purification (METCR/Prep001) (P2) LC was performed using a Waters Sunfire C18 column (30 mm x 100 mm, 5 μm; temperature: room temperature) for 0.55 min in an injection volume of 1500 μL at a flow rate of 40 mL/min. A gradient of 30% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 30 - 95% B over 10.45 minutes and held for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.21 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 3 (P3): Basic Initial Method

Purification (METCR/Prep002) (P3) LC was performed using a Waters 10% B (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) followed by a gradient of 10 - 95% B over 13.89 minutes and held for 2.11 minutes. A second gradient of 95 - 10% B was then applied over 0.2 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

Purification Method 4 (P4): Basic Standard Method

Purification (METCR/Prep003) (P4) LC was performed using a Waters A gradient of 30% B over 10.45 minutes (A = 0.2% ammonium hydroxide in water; B = 0.2% ammonium hydroxide in acetonitrile) followed by a gradient of 30 - 95% B over 10.45 minutes and held for 2.10 minutes. A second gradient of 95 - 30% B was then applied over 0.21 minutes. UV spectra were recorded at 215 nm using a Gilson detector.

LCMC for analysis were collected using one of the following methods.

Method 1 (M1): Acid IPC Method (METCR1410 - MS17, MS18, MS19)

Analysis (MET/CR/1410) (M1) HPLC-MS was performed using a Kinetex Core Shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40°C) with 3 μL of A gradient of 5 - 100% B (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.1 min was performed in the injection volume over 1.2 min. A second gradient of 100 - 5% B was then applied over 0.01 minutes and held for 0.39 minutes. UV spectra were recorded at 215 nm using SPD-M20A PDA detector, spectral range: 210 - 400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 2 (M2):

Mass spectrometry data was collected using a Waters Acquity H-Class ultra high pressure liquid chromatograph coupled to a Waters Acquiti TQD mass spectrometer. Samples were separated and resolved using an Acquity UPLC BEH C18 column (2.1 x 50 mm). Compounds were eluted from the column using a 10-minute linear solvent gradient: 0-0.5 min, 5% B; 0.5 - 6.5 min, 100% B, 6.5-7.5 min; 100% B, 7.5-8.1 min; 5% B, 8.1-10 min; 5% B. Solvent flow rate is 0.45 mL per minute. Solvent A was water and solvent B was acetonitrile. Mass spectra were collected in positive or negative ion mode with the following parameters: 2.5 kV capillary voltage; 25 V sampling cone voltage; 140°C source temperature; 400°C desolvation temperature; Nitrogen desolvation at 800 L/hr.

Method 3 (M3): Basic IPC method (MET-uPLC-AB-2005 - MS16, MSQ5)

Analysis (MET/uPLC/AB2005) (M14) uHPLC-MS was performed using a Waters uPLC® BEHTM C18 column (2.1 mm x 30 mm, 1.7 μm; temperature 40°C), 1 μL injection at a flow rate of 1.0 mL/min. A gradient of 1 - 100% B in volume over 1.1 minutes (A = 2 mM ammonium bicarbonate in water, buffered to pH 10; B = acetonitrile) followed by 100% B over 0.25 minutes was performed. A second gradient of 100 - 1% B was then applied over 0.05 minutes and held for 0.4 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm. Mass spectra were obtained using a Waters Quatro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MathLynx and OpenLynx software.

Method 4 (M4): Acidic Final Analytical Method (METCR-uPLC-AB101 - MSQ1, MSQ2, MSQ4)

Analysis (MET/uPLC/AB101) (M4) uHPLC-MS was performed using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μm; temperature: 40°C) at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5.3 min (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.5 min was performed in an injection volume of 1 μL. A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm, and ELS data were collected on a Waters Acquity ELS detector when reported. Mass spectra were obtained using Waters SQD or Waters Acquity QDA. Data were integrated and reported using Waters MathLynx and OpenLynx software.

Method 5 (M5): Acidic Final Analytical Method (METCR1416 - MS18, MS19)

Analysis (MET/CR/1416) (M5) HPLC-MS was performed using a Waters Atlantis dC18 column (2.1 mm x 100 mm, 3 μm; temperature: 40°C) with an injection volume of 3 μL at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5 minutes (A = 0.1% formic acid in water; B = 0.1% formic acid in acetonitrile) followed by 100% B over 0.4 minutes was performed. A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.58 minutes. UV spectra were recorded at 215 nm using SPD-M20A PDA detector, spectral range: 210 - 400 nm. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

Method 6 (M6): Basic Final Analysis Method (MET-uPLC-AB105 - MS16, MSQ5)

Analysis (MET/uHPLC/AB105) (M8) uHPLC-MS was performed using a Waters uPLC® BEHTM C18 column (2.1 mm x 100 mm, 1.7 μm column; temperature: 40°C) at a flow rate of 0.6 mL/min. A gradient of 5 - 100% B over 5.3 minutes (A = 2 mM ammonium bicarbonate in water, buffered to pH 10; B = acetonitrile) followed by 100% B over 0.5 minutes was performed at an injection volume of . A second gradient of 100 - 5% B was then applied over 0.02 minutes and held for 1.18 minutes. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, spectral range: 200 - 400 nm. Mass spectra were obtained using a Waters Quatro Premier XE mass detector or a Waters SQD2. Data were integrated and reported using Waters MathLynx and OpenLynx software.

SFC chiral resolution was performed using the following method: Column: Daicel Chiralpak IG, 250 mm x 20 mm ID, 5 μm; Mobile phase A: CO ₂ / MeOH [0.2% NH ₃ (7M solution in MeOH)] = 70/30; Flow rate: 60 g/min; 214 nm. Temperature: 35℃.

Unless otherwise stated, ¹ H nuclear magnetic resonance spectroscopy (NMR) spectra were obtained on a Bruker Avance III HD 500 MHz spectrometer, Bruker™ 300 MHz, or 500 MHz. , recorded on 400 MHz or 250 MHz. Chemical shifts δ are quoted in parts per million (ppm) relative to TMS and are calibrated using residual non-deuterated solvent as an internal reference. The following abbreviations are used to indicate multiplicity and general assignment: s (singlet), d (doublet), t (triple), q (quartet), dd (doublet of a doublet), ddd (doublet of a doublet) doublet), dt (doublet of triplets), dq (doublet of quartets), hep (septet), m (multiplet), pent (quintet), td (triplet of doublets), qd (quartet of doublets) ), app. (obvious) and br. (broadness). The coupling constant J is rounded to the nearest 0.1 Hz.

Example 117

General synthesis reaction scheme

Several methods for preparing compounds of the invention are illustrated in the Schemes and Examples below. The invention further provides a process for the preparation of compounds of structural formula (I) as defined above. In some cases, the order in which the above schemes are performed can be varied to facilitate the reaction or avoid unwanted reaction products. The following examples are provided for illustrative purposes only and should not be construed as limiting the disclosed invention.

Scheme A

Compounds of formula (A-6) are prepared starting from the dichlorocarboxylic acid ester A-1 using various substituted phenols in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH or other organic bases. It can be synthesized in a five-step linear synthesis by nucleophilic substitution of Cl adjacent to the carboxylic acid to give the intermediate of type A-2. The intermediate of type A-2 was further treated with HI (50%), HI (57%) or HI (40%) to give the intermediate of type A-3. Variously substituted R ₃ groups can be introduced by Pd-mediated or Cu-mediated coupling with intermediates of type A-3. Carboxylic acids of intermediate type A-5 can be prepared by hydrolyzing the ester intermediate of type A-4 using a base such as aqueous NaOH, KOH or LiOH. Alternatively, intermediate of type A-5 can be prepared by treating intermediate A-4 with aqueous 1-6N HCl. The carboxylic acid (A-5) is activated with acid chloride and coupled with R ₂ NH ₂ , or the carboxylic acid (A-5) is activated in an organic solvent and base such as DIEA, Et ₃ N, DMAP or pyridine. A-6 can be obtained by coupling with R ₂ NH ₂ using standard amide coupling reagents, including but not limited to HATU, TBTU, EDC or T ₃ P.

Scheme B

Alternatively, compounds of formula (A-6) can be prepared by the Cl intermediate of type B-1 using various substituted phenols in the presence of a base such as K ₂ CO ₃ , Cs ₂ CO ₃ , NaH, KH or other organic bases. Nucleophilic substitution of can be made to provide an intermediate of type B-2. Carboxylic acids of intermediate type B-3 can be prepared by hydrolyzing the ester intermediate of type B-2 using a base such as aqueous NaOH, KOH or LiOH. Alternatively, intermediate of type B-3 can also be prepared by treating intermediate B-2 using aqueous 1-6N HCl. The carboxylic acid (B-3) is activated with acid chloride and coupled with R ₂ NH ₂ , or the carboxylic acid (B-3) is activated in an organic solvent and base such as DIEA, Et ₃ N, DMAP or pyridine. A-6 can be obtained by coupling with R ₂ NH ₂ using standard amide coupling reagents, including but not limited to HATU, TBTU, EDC or T ₃ P.

Scheme C

Alternatively, compounds of type A-6 can also be prepared by activating the carboxylic acid (C-1) with acid chloride and coupling it with R ₂ NH ₂ , or by activating the carboxylic acid (C-1) with organic solvents and bases. , can be prepared by coupling with R ₂ NH ₂ to give C-2 using standard amide coupling reagents, such as but not limited to HATU, TBTU, EDC or T ₃ P among DIEA, Et ₃ N, DMAP or pyridine. there is. Compounds of type A-6 can be obtained by treating intermediates of type C-2 with various phenols in the presence of bases such as NaH, K ₂ CO ₃ , Cs ₂ CO ₃ , DIEA or Et ₃ N using organic solvents. there is.

Example 118

Specific synthesis:

Intermediate 1: 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid

Reagents & Conditions: Reagents & Conditions: a) 4-fluoro-2-methoxy-phenol, K ₂ CO ₃ , CH ₃ CN, 60°C, 7 hours; b) HI (55%), 40°C, 24 hours; c) Methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, TBAI, CuI, DMF, 90° C., 2 hours; d) LiOH, THF, H ₂ O, room temperature, 24 hours.

Step 1: Methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate.

4-Fluoro-2-methyl-phenol (3.01 g, 23.8 mmol), methyl 3,6-dichloropyridazine-4-carboxylate (4.70 g, 22.7 mmol) and potassium carbonate (47 mL) in acetonitrile (47 mL) The mixture (4.71 g, 34.1 mmol) was stirred at 80°C for 3 hours.

The reaction was cooled to room temperature, filtered, and washed with MeCN (20 mL). The filtrate was concentrated under vacuum to give a crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 15% EtOAc in heptane gave the title compound methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate. (95.0%) (4.10 g, 58%) was obtained as a light yellow oil. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (s, 1H), 7.29 - 7.20 (m, 2H), 7.16 - 7.06 (m, 1H), 3.94 (s, 3H), 2.11 (s, 3H) ). LC-MS: m/z: 297/299 [M+H] ⁺ .

Step 2: Methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate.

6-Chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (95%, 4.10 g, 13.1 mmol) in 55% aqueous hydrogen iodide (50 mL, 0.197 mol) ) The mixture was stirred at 40°C for 3 hours. The mixture was left at room temperature overnight. The reaction mixture was filtered. The filter cake was washed with water. The solid was redissolved in 55% aqueous hydrogen iodide (50 mL, 0.197 mol) and stirred at 40° C. for 24 hours. The mixture was cooled to room temperature, filtered, and the solid was washed with water and dried in a high vacuum oven at 40° C. overnight to obtain methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine- 4-Carboxylate (79.0%) (2.70 g, 42%) was obtained as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 7.26 - 7.17 (m, 2H), 7.15 - 7.05 (m, 1H), 3.91 (s, 3H), 2.09 (s, 3H) ). MS: m/z: 388.9 [M+H] ⁺ .

Step 3: Methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: DMF (10 mL) (degassed with nitrogen for 5 min) ) of methyl 3-(4-fluoro-2-methyl-phenoxy)-6-iodo-pyridazine-4-carboxylate (80%, 2.70 g, 5.57 mmol), CuI (1.6g, 8.35 mmol) ), tetrabutylammonium; methyl difluoro(fluorosulfonyl)acetate (5.34g, 27.8 mmol) was added to a mixture of iodide (0.824 g, 2.23 mmol), and stirred at 90°C for 2 hours. The reaction was cooled to room temperature, filtered, and washed with EtOAc (2 x 10 mL). The filtrate was washed with brine (50 mL), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 50% EtOAc in heptane gave the title compound methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine- 4-Carboxylate (99.0%) (0.770 mg, 41%) was obtained as a light yellow solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.54 (s, 1H), 7.32 - 7.20 (m, 2H), 7.14 (td, J = 8.5, 3.2 Hz, 1H), 3.97 (s, 3H), 2.13 (s, 3H). MS: m/z: 316.95 [M+H]+, (ESI+). Unreacted starting material methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (220 mg, 13%) was recovered as a light yellow oil.

Step 4: 3-(4-Fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid.

THF (7.92 mL): Methyl 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate (99%, 770%) in water (1.98 mL) mg, 2.31 mmol), lithium hydroxide (288 mg, 11.5 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was diluted with water (10 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The solid was filtered, washed with water (2 x 10 mL), dissolved in EtOAc (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound 3-(4-fluoro-2-methyl -Phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (99.0%) (640 mg, 87%) was obtained as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 7.31 - 7.22 (m, 2H), 7.18 - 7.09 (m, 1H), 2.12 (s, 3H). LC-MS: m/z 316.95 [M+H] ⁺ , (ESI+), RT = 1.06 Method METCR1410 typical 2 min.

Intermediate 2: 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid

Reagents & Conditions: a) 4-Fluoro-2-methoxy-phenol, K ₂ CO ₃ , CH ₃ CN, 60°C, 7 hours; b) SOCl ₂ , MeOH, 50°C; c) HI (55%), 40°C, 24 hours; d) Methyl 2,2-difluoro-2-(fluorosulfonyl) acetate, TBAI, CuI, DMF, 90° C., 2 hours; e) LiOH, THF, H ₂ O, room temperature, 24 hours.

Step 1: 6-Chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylic acid.

To a solution of 4-fluoro-2-methoxyphenol (1.2 mL, 10.4 mmol) in DMF (20.7 mL) was added sodium hydride (60%) (0.622 g, 15.5 mmol) under nitrogen and the solution was incubated at room temperature for 30 °C. Stirred for minutes. To the resulting mixture was added 3,6-dichloropyridazine-4-carboxylic acid (1.00 g, 5.18 mmol) and stirring was continued for an additional 66 hours at room temperature. At the end of this period, water (200 mL) was added and pH was adjusted to 1 using HCl (6N). The mixture was extracted with EtOAc (4 x 40 mL). The combined extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The crude mixture was purified by column chromatography on SiO2 with a gradient of 0-80% EtOAc in heptane to give the title compound 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-car. Boxylic acid (1.211 g, 74%) was obtained as a light red solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.32 (s, 1H), 7.27 (dd, J = 8.8, 5.8 Hz, 1H), 7.12 (dd, J = 10.7, 2.9 Hz, 1H), 6.84 ( td, J = 8.5, 2.9 Hz, 1H), 3.71 (s, 3H). LC-MS: m/z 299.0/301.0 [M+H] ⁺ , (ESI+).

Step 2: Methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate.

6-Chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylic acid (500 mg, 1.77 mmol) was dissolved in DCM (12.2 mL) and thionyl chloride (5.1 mL). , 70.8 mmol) was added in 1 portion at room temperature and the resulting mixture was stirred at 50° C. for 8 hours. Additional thionyl chloride (2.5 mL, 35 mmol) was added and the reaction was stirred at 50° C. for an additional 1 hour. The mixture was allowed to cool to 0° C. and anhydrous methanol (5.48 mL) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water (20 mL) followed by saturated aqueous Na ₂ CO ₃ (20 mL), the layers were separated and the organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of EtOAc in heptane to give methyl 6-chloro-3-(4-fluoro-2-methyl-phenoxy)pyridazine-4-carboxylate (335 mg, 64%) was obtained as an off-white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (s, 1H), 7.25 - 7.18 (m, 2H), 7.10 (td, J = 8.6, 3.1 Hz, 1H), 3.92 (s, 3H), 2.09 (s, 3H). LC-MS: m/z 297.3 [M+H] ⁺ , (ESI+), RT = 1.21 METCR1410 typical 2 min.

Step 3: Methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate.

Methyl 6-chloro-3-(4-fluoro-2-methoxy-phenoxy)pyridazine-4-carboxylate (8.10 g, 23.3 mmol) in 55% aqueous hydrogen iodide (18 mL, 0.350 mol) The mixture was stirred at 40°C for 24 hours. The mixture was cooled to room temperature and filtered. The solid was washed with water and dried in a high vacuum oven at 40° C. overnight to give the title compound methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate (12.58 g, 88%) was obtained as an orange solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 7.25 (m, 1H), 7.13 - 7.09 (m, 1H), 6.84 - 6.79 (m, 1H), 3.90 (s, 3H) ), 3.70 (s, 3H). LC-MS: m/z: 404.9 [M+H]+, (ESI+), RT = 1.19, METCR1410 typical 2 min.

Step 4: Methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate: DMF (72 mL) (degas with nitrogen for 5 min) methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-iodo-pyridazine-4-carboxylate (13.34 g, 21.8 mmol), copper iodide (6.26 g, To a mixture of 32.7 mmol) and tetrabutylammonium iodide (3.23 g, 8.71 mmol), methyl difluoro(fluorosulfonyl)acetate (20.92 g, 0.109 mol) was added and stirred at 90°C for 2 hours. did. The reaction was cooled to room temperature, poured into water (200 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to give a crude residue. Purification by chromatography on silica eluting with a gradient of 0 to 50% EtOAc in heptane gave the title compound (95.0%) (2.85 g, 36%) as a light orange solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 7.32 (dd, J = 8.8, 5.8 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 ( td, J = 8.5, 2.9 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 3H). LC-MS: m/z 347.3 [M+H] ⁺ , (ESI+), RT = 3.57 MET-uPLC-AB-105 (7 min, high pH).

Step 5: 3-(4-Fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid.

Methyl 3-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4- in THF:H ₂ O (4:1; v/v) (40 mL) To a mixture of carboxylates (2.85 g, 7.82 mmol), lithium hydroxide (0.98 g, 39.1 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction was diluted with water (40 mL) and the pH was adjusted to 1 by dropwise addition of 1M HCl. The product was extracted with EtOAc (3 x 60 mL), dried (MgSO ₄ ), filtered, and the solvent was evaporated under reduced pressure to give the title compound 3-(4-fluoro-2-methoxy-phenoxy)-6-. (Trifluoromethyl)pyridazine-4-carboxylic acid (90.0%) (2.35 g, 82%) was obtained as an orange solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 7.24 (dd, J = 8.8, 5.9 Hz, 1H), 7.12 (dd, J = 10.7, 2.8 Hz, 1H), 6.84 ( dt, J = 8.5, 4.2 Hz, 1H), 3.71 (s, 4H). LC-MS: m/z 332.95 [M+H] ⁺ , (ESI+), RT = 1.03 Method XX METCR1410 typical 2 min.

Example 119

Compound 1: tert-Butyl (R)-3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)piperidine- 1-carboxylate

Reagents & Conditions: tert-Butyl (3R)-3-aminopiperidine-1-carboxylate, HATU, DIEA, DCM, room temperature, 2 hours.

N-ethyl-N-isopropyl-propan-2-amine (0.12 mL, 0.696 mmol), 3-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridazine-4 -A mixture of carboxylic acid (100 mg, 0.316 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (76 mg, 0.379 mmol) was incubated in DCM (5 mL) at room temperature under nitrogen. dissolved in it. N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (144 mg , 0.379 mmol) was added in 1 portion. The reaction mixture was stirred at room temperature for 2 hours. The solvent was reduced to 2 mL under vacuum. Purified by chromatography on silica, eluting with a gradient of 0 to 100% EtOAc in heptane, tert-butyl (3R)-3-[[3-(4-fluoro-2-methyl-phenoxy)-6-( Trifluoromethyl)pyridazine-4-carbonyl]amino]piperidine-1-carboxylate (95.0%) (140 mg, 0.267 mmol, 84% yield) was obtained as an off-white solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.76 (d, J = 7.5 Hz, 1H), 8.37 (s, 1H), 7.30 (dd, J = 9.0, 5.0 Hz, 1H), 7.25 (dd, J = 9.3, 3.1 Hz, 1H), 7.15 (dt, J = 8.5, 4.3 Hz, 1H), 3.89 - 3.77 (m, 2H), 3.60 - 3.51 (m, 1H), 3.09 - 2.92 (m, 2H) , 2.12 (s, 3H), 1.93 - 1.84 (m, 1H), 1.73 - 1.65 (m, 1H), 1.59 - 1.30 (m, 11H). LC-MS: m/z 496.95 [MH] ⁺ , (ESI-), RT = 1.36 METCR1410 typical 2 min.

Compound 2: (R)-3-(4-fluoro-2-methylphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide

Reagents & Conditions: a) 2,2,2-trifluoroacetic acid, DCM, room temperature, 3 hours.

tert-Butyl (R)-3-(3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)piperidine-1-car Boxylate (0.130 g, 0.248 mmol) and 2,2,2-trifluoroacetic acid (0.37 mL, 4.96 mmol) were stirred in DCM (3.92 mL) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum and the residue was dissolved in DCM (10 mL) and washed with saturated NaHCO ₃ (10 mL) and brine (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (R)-3-(4-fluoro-2-methylphenoxy)-N-(piperidin-3-yl). -6-(Trifluoromethyl)pyridazine-4-carboxamide (0.075 g, 72%) was obtained as an off-white solid. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.67 (d, J = 7.9 Hz, 1H), 8.41 (s, 1H), 7.31 (dd, J = 8.9, 5.0 Hz, 1H), 7.25 (dd, J = 9.3, 3.1 Hz, 1H), 7.14 (td, J = 8.5, 3.1 Hz, 1H), 3.89 - 3.79 (m, 1H), 2.96 (dd, J = 11.8, 3.4 Hz, 1H), 2.71 (dt) , J = 12.1, 4.3 Hz, 1H), 2.48 - 2.42 (m, 2H), 2.31 - 2.18 (m, 1H), 2.13 (s, 3H), 1.89 - 1.79 (m, 1H), 1.67 - 1.56 (m , 1H), 1.52 - 1.34 (m, 2H). LC-MS: m/z 399.0 [M+H]+, (ESI+), RT = 2.95 MET-uPLC-AB-101 (7 min, low pH).

Compound 3: (R)-3-(4-fluoro-2-methylphenoxy)-N-(1-(methylsulfonyl)piperidin-3-yl)-6-(trifluoromethyl)pyri Minced-4-carboxamide

Reagents and conditions: MeSO ₂ Cl, DMAP, Et ₃ N, DCM, room temperature.

Triethylamine (0.015 mL, 0.107 mmol), (R)-3-(4-fluoro-2-methylphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl) A mixture of pyridazine-4-carboxamide (0.030 g, 0.0715 mmol) and methanesulfonyl chloride (0.0083 mL, 0.107 mmol) was dissolved in DCM (2 mL) under nitrogen at room temperature. N,N-dimethylpyridin-4-amine (8.7 mg, 0.0715 mmol) was added to the mixture and stirring was continued for an additional 1 hour at room temperature. The solvent was removed under vacuum. Purification by preparative LC gave the title compound (R)-3-(4-fluoro-2-methylphenoxy)-N-(1-(methylsulfonyl)piperidin-3-yl)-6-( Trifluoromethyl)pyridazine-4-carboxamide (0.019 g, 57%) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.87 (d, J = 7.7 Hz, 1H), 8.41 (s, 1H), 7.30 (dd, J = 8.9, 5.1 Hz, 1H), 7.24 (dd, J = 9.4, 3.0 Hz, 1H), 7.14 (td, J = 8.6, 3.1 Hz, 1H), 4.09 - 3.96 (m, 1H), 3.56 (dd, J = 11.4, 3.7 Hz, 1H), 3.32 - 3.22 (m, 1H), 2.97 - 2.89 (m, 1H), 2.87 (s, 3H), 2.82 (dd, J = 11.4, 8.3 Hz, 1H), 2.12 (s, 3H), 1.90 - 1.78 (m, 2H) ), 1.66 - 1.46 (m, 2H). LC-MS: m/z 477.0 [M+H]+, (ESI+), RT = 4.1 MET-uPLC-AB-101 (7 min, low pH). [Initial elution method:- Column: SunfireTM preparative C18 10 um OBDTM, 30 x 100 mm; Mobile phase: 5-95% acetonitrile (0.1% formic acid) in water (0.1% formic acid) over 14 minutes, flow rate: 40 mL/min UV: 215 and 254 nm)

Compound 4: (R)-N-(1-acetylpiperidin-3-yl)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4- Carboxamide

Reagents & Conditions: a) Ac ₂ O, Et ₃ N, DCM, DMAP, room temperature.

Acetic anhydride (0.0099 mL, 0.107 mmol), (R)-3-(4-fluoro-2-methylphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyri A mixture of minced-4-carboxamide (0.030 g, 0.0715 mmol) and triethylamine (0.015 mL, 0.107 mmol) was dissolved in DCM (2 mL) at room temperature under nitrogen and DMAP (0.0087 g, 7.15 μmol) was added. Added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum. Purification by preparative LC method A gave the title compound (R)-N-(1-acetylpiperidin-3-yl)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoro Romethyl)pyridazine-4-carboxamide (0.015 g, 49%) was obtained as a white solid. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (bs, 1H), 8.30 (s, 1H), 7.28 (dd, J = 8.9, 5.0 Hz, 1H), 7.20 (dd, J = 9.4, 3.1 Hz, 1H), 7.10 (td, J = 8.5, 3.1 Hz, 1H), 4.04 - 3.74 (m, 2H), 3.59 - 3.49 (m, 1H), 3.40 - 3.19 (m, 2H), 2.15 (s, 3H), 2.02 - 1.91 (m, 4H), 1.78 - 1.61 (m, 2H), 1.59 - 1.44 (m, 1H). LC-MS: m/z 441.0 [M+H]+, (ESI+), RT = 3.94 MET-uPLC-AB-101 (7 min, low pH).

Compound 5: tert-Butyl (S)-3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)piperidine -1-carboxylate

Reagents & Conditions: tert-Butyl (3S)-3-aminopiperidine-1-carboxylate, DIEA, DCM, room temperature.

3-(4-Fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (140 mg, 0.421 mmol), tert-butyl (3S)-3- A mixture of aminopiperidine-1-carboxylate (101 mg, 0.506 mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.16 mL, 0.927 mmol) was dissolved in DCM (2.1071 mL) under nitrogen. Dissolved at room temperature. N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate (192 mg , 0.506 mmol) was added in 1 portion. The reaction mixture was stirred at room temperature for 2 hours. IPC1 LCMS indicated formation of the desired product. The reaction mixture was purified directly by chromatography on silica (10 g Spa Duo) eluting with a gradient from 0 to 50% EtOAc in heptane to give tert-butyl (3S)-3-[[3-(4-fluoro-2- Methoxy-phenoxy)-6-(trifluoromethyl)pyridazine-4-carbonyl]amino]piperidine-1-carboxylate (95.0%) (182 mg, 80%) was obtained as a colorless oil. did. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 (d, J = 7.6 Hz, 1H), 8.34 (s, 1H), 7.34 (dd, J = 8.8, 5.9 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.90 - 3.76 (m, 2H), 3.73 (s, 3H), 3.58 - 3.51 (m, 1H), 3.09 - 2.96 (m, 2H), 1.97 - 1.84 (m, 1H), 1.77 - 1.65 (m, 1H), 1.61 - 1.41 (m, 2H), 1.37 (s, 9H). m/z 513.6 [M+H]+, (ESI+), RT = 4.06 MET-uPLC-AB-105 (7 min, high pH).

Compound 6: (S)-3-(4-fluoro-2-methoxyphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxyx amides

Reagents & Conditions: a) 2,2,2-trifluoroacetic acid, DCM, room temperature, 3 hours.

The title compound was reacted with tert-butyl (S)-3-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)piperidine. It was prepared by a similar procedure described for compound 2 using -1-carboxylate. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.64 (d, J = 7.8 Hz, 1H), 8.37 (s, 1H), 7.35 (dd, J = 8.8, 5.9 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 3.96 - 3.76 (m, 2H), 3.73 (s, 3H), 2.99 (m, 2H), 2.75 (m , 1H), 2.46 (m, 1H), 1.84 (m, 1H), 1.63 (s, 1H), 1.56 - 1.33 (m, 2H). m/z 415.3 [M+H]+, (ESI+), RT = 3.09 MET-uPLC-AB-105 (7 min, high pH).

Compound 7: (S)-3-(4-fluoro-2-methoxyphenoxy)-N-(1-(methylsulfonyl)piperidin-3-yl)-6-(trifluoromethyl) Pyridazine-4-carboxamide

Reagents & Conditions: a) MeSO ₂ Cl, DMAP, DCM, room temperature, 1 hour.

The title product was reacted with (S)-3-(4-fluoro-2-methoxyphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid. It was prepared by a similar procedure described for compound 3 using amide and methanesulfonyl chloride. ^1H NMR (500 MHz, DMSO-d ₆ ) δ 8.83 (d, J = 7.7 Hz, 1H), 8.38 (s, 1H), 7.34 (dd, J = 8.8, 5.8 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.87 (td, J = 8.5, 2.9 Hz, 1H), 4.00 (m, 1H), 3.72 (s, 3H), 3.57 (dd, J = 11.2, 3.9 Hz, 2H) ), 2.94 - 2.88 (m, 1H), 2.87 (s, 3H), 2.80 (dd, J = 11.3, 8.4 Hz, 1H), 1.91 - 1.76 (m, 2H), 1.65 - 1.45 (m, 2H). m/z 492.9 [M+H]+, (ESI+), RT = 4.06 METCR1416 Hi res 7 min.

Compound 8: (S)-N-(1-acetylpiperidin-3-yl)-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4 -Carboxamide

Reagents & Conditions: a) Ac ₂ O, Et ₃ N, DCM, DMAP, room temperature.

The title product was reacted with (S)-3-(4-fluoro-2-methoxyphenoxy)-N-(piperidin-3-yl)-6-(trifluoromethyl)pyridazine-4-carboxylic acid. Prepared by a similar procedure described for compound 4 using amide and acetic anhydride. ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.28 (s, 1H), 7.33 (dd, J = 8.8, 5.8 Hz, 1H), 7.10 (dd, J = 10.6, 2.9 Hz, 1H), 6.86 (td, J = 8.5, 2.9 Hz, 1H), 4.03 - 3.85 (m, 2H), 3.74 (s, 3H), 3.60 - 3.45 (m, 1H), 3.25 (d, J = 34.9 Hz, 2H), 1.97 (s, 3H), 1.95 - 1.87 (m, 1H), 1.68 (dd, J = 11.5, 7.7 Hz, 2H), 1.51 (s, 1H). m/z 457.0 [M+H]+, (ESI+), RT = 3.85 METCR1416 Hi res 7 min.

The compounds listed in Table 28 were prepared by similar procedures described for Compound 1 using the appropriate starting materials.

Table 28

Example 120

Compound profiling for NaV1.8 - Human NaV1.8 cell line - SynchroPatch384PE assay

Compounds were tested on recombinant human Nav1.8 stably transfected HEK cells using the SynchroPatch384PE system, an automated patch clamp device. Cells were cultured at 37°C/5% CO2 in DMEM medium supplemented with Glutamax I, 1% NEAA, and 10% FBS and seeded in T175 flasks. After culturing the cells at 30°C for 1 day, sodium currents were recorded. On the day of recording, cells were detached with 0.05% trypsin-EDTA, resuspended in serum-free DMEM medium, placed in a SynchroPatch384PE 6°C pre-chilled cell hotel, and shaken at 200 rpm. Intracellular solution (IC) was 10, CsCl; 110, CsF; 20, EGTA; 10, contained HEPES at mM. Extracellular solution (EC) was 140, NaCl; 4, KCl; 5 glucose; 10, HEPES; 2, CaCl ₂ ; 1, contained MgCl ₂ in mM. Wash solutions were 40, NMDG; 100, NaCl; 4, KCl; 10, glucose; 10, HEPES; 5, CaCl ₂ ; 1, contained MgCl ₂ in mM.

Compounds were tested in quadruplicate in 0.1% DMSO and 0.03% pluronic acid. Compounds were diluted 1:3.33 in EC solution to generate a 10-point concentration response curve over a final concentration range of 10-0.0002 μM in the assay plate. Compounds with low nM potency were retested using a lower concentration range (1-0.00002 μM). Each plate contained tetracaine and another instrumental compound as a positive control. Up to 7 compounds were tested on one plate. 150 μM tetracaine and 0.1% DMSO were used as high and low controls, respectively.

Whole-cell patch clamp recordings were performed according to Nanion's standard procedures for SynchroPatch384PE®. Cells were maintained at a holding potential of -120 mV. A depolarizing step to 10 mV for 30 ms was applied (P1 measurement), followed by a hyperpolarizing step to -100 mV for 100 ms. Apply a 10 s inactivation step at -40 mV, followed by stepping to -100 mV for 20 ms, then stepping to 10 mV for 30 ms (P2 measurement), then returning to -100 mV for 30 ms. I ordered it. The sweep interval was 15 seconds with a sampling rate of 10 kHz. After establishment of whole-cell composition in EC, two washing steps with baseline buffer were performed to stabilize the baseline. Compounds were then applied to each well by SynchroPatch and currents were recorded in EC for 5 minutes before tetracaine was applied to achieve complete block at the end of the experiment. The potency of the compounds was assessed in two readouts, resting state block (P1 measurement) or inactivation state block (P2 measurement) to obtain IC50 values. Values were normalized to high (tetracaine) and low (DMSO) controls. Table 28 shows the potency of compounds against human NaV1.8.

Table 29 presents the potency of compounds against human NaV1.8, where “A” represents an IC50 of 200 nM or less, “B” represents an IC50 of greater than 201 nM and less than or equal to 500 nM, and “C” represents an IC50 of 501 nM or less. Indicates an IC50 greater than nM and up to 1000 nM, “D” indicates an IC50 greater than 1001 nM and up to 5000 nM, and “E” indicates an IC50 greater than 5001 nM.

Table 29

E. Examples of the Fifth Set of Compounds

Example 121

synthesis procedure

Exemplary compounds were prepared via several general synthetic routes shown in the Examples below. Any of the disclosed compounds of the invention can be prepared according to one or more of these synthetic routes or specific examples, or via modifications thereof accessible to those skilled in the art.

Method A

Step 1: 4-Bromo-6-(trifluoromethyl)pyridazin-3(2H)-one

6-(trifluoromethyl)pyridazin-3(2H)-one (9.00 g, 54.8 mmol, 1.00 eq), 4 Angstrom molecular sieve (18.0 g) and dibromohydantoin (20.3 g, 71.3 mmol, 1.30 eq) Equivalents) were added to acetic acid (37.0 mL) and acetonitrile (863 mL) and the mixture was stirred at 60° C. for 48 hours. The reaction mixture was diluted with water (1.00 L) and extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with brine (1.50 L), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 to 15/1) to give the desired product (7.00 g, 28.8 mmol, 52.5% yield) as a yellow solid.

¹ H NMR: 400 MHz CDCl _{3 δ} - 12.22 (s, 1H), 7.86 (s, 3H).

MS, ES ⁺ m/z 243 (M+H) ⁺

Step 2: Methyl 3-oxo-6-(trifluoromethyl)-2,3-dihydropyridazine-4-carboxylate

Autoclave Xantphos (500 mg, 864 μmol, 0.042 eq), Pd(OAc) ₂ (115 mg, 514 umol, 0.0250 eq) and triethylamine (4.16 g, 41.1 mmol, 5.73 mL, 2.00 eq) were added and the mixture was incubated at 80°C with CO (50 eq). psi) for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=30/1 to 0/1) to obtain the target compound (2.50 g, 11.2 mmol, 54.7 % yield) was obtained as a yellow solid.

¹ H NMR: 400 MHz CDCl _{3 δ} 12.54 (s, 1H), 8.11 (s, 1H), 3.99 (s, 3H).

MS, ES ⁺ m/z 223 (M+H) ⁺

Step 3: Methyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate

of methyl 3-oxo-6-(trifluoromethyl)-2,3-dihydropyridazine-4-carboxylate (1.50 g, 6.75 mmol, 1.00 eq) in 1,4-dioxane (15.0 mL) Phosphorus oxychloride (10.3 g, 67.5 mmol, 6.28 mL, 10.0 equiv) was added to the solution at 0°C, and the mixture was stirred at 100°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with saturated sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1 to 8/1) to give the desired product (1.00 g, 4.16 mmol, 61.6% yield) as a yellow oil.

¹ H NMR: 400 MHz CDCl _{3 δ} - 8.17 (s, 1H), 4.06 (s, 3H).

MS, ES ⁺ m/z 241 (M+H) ⁺

Step 4: Methyl 3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylate

To a solution of methyl 3-chloro-6-(trifluoromethyl)pyridazine-4-carboxylate (500 mg, 2.1 mmol) in acetonitrile (10 mL) was added 4-fluoro-2-methoxy-phenol ( 325 mg, 2.3 mmol, 1.1 equiv) and cesium carbonate (680 mg, 2.1 mmol, 1.0 equiv) were added. The resulting mixture was heated to 50°C for 2 hours. After cooling to room temperature, the mixture was diluted with water (75 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product. It was used without further purification, and quantitative yield was assumed.

MS, ES ⁺ m/z 347 (M+H) ⁺

Step 5: 3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid

The crude product from step 4 (719 mg, 2.1 mmol) was dissolved in methanol (15 mL) and water (5 mL) and excess solid sodium hydroxide was added. The resulting mixture was stirred at room temperature for 2 hours. The resulting solution was diluted with water (75 mL), and 6N hydrochloric acid was carefully added to adjust the pH to ~2, allowing a precipitate to form. It was collected by filtration, rinsed with water and dried under reduced pressure to give the desired product (350 mg, 1.1 mmol, 51% yield) as a white solid.

MS, ES ⁺ m/z 333 (M+H) ⁺

Step 6: 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide

3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxylic acid (350 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL). Oxalyl chloride (0.1 mL, 1.2 mmol) and N,N-dimethylformamide (1 drop) were added and the mixture was allowed to stir at room temperature for 1 hour. The mixture was cooled in an ice bath and 3-methylsulfanylaniline (161 mg, 1.2 mmol) and N,N-diisopropylethylamine (272 mg, 2.1 mmol) were added dropwise as a solution in dichloromethane (5 mL). The mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (SiO ₂ , dichloromethane/methanol, 0-5%) to give the desired product (355 mg, 0.8 mmol, 74% yield) as a solid. did.

MS, ES ⁺ m/z 454 (M+H) ⁺

Step 7: 3-(4-fluoro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carbox amides

3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylthio)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide in methanol (10 mL) To a solution of (355 mg, 0.8 mmol) was added ammonium carbonate (113 mg, 1.2 mmol, 1.5 equiv) and iodobenzene diacetate (580 mg, 1.8 mmol, 2.3 equiv). The mixture was allowed to stir at room temperature for 2 hours and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO ₂ , dichloromethane/methanol, 0-12%) to obtain the desired product (189 mg, 0.4 mmol, 50% yield) as a solid.

¹ H NMR (400 MHz, DMSO-d6) d ppm 3.07 (d, J=0.76 Hz, 3 H) 3.74 (s, 3 H) 4.29 (s, 1 H) 6.83 - 6.94 (m, 1 H) 7.17 ( dd, J=10.74, 2.91 Hz, 1 H) 7.39 (dd, J=8.84, 5.81 Hz, 1 H) 7.65 (t, J=7.96 Hz, 1 H) 7.69 - 7.77 (m, 1 H) 7.93 (ddd , J=8.02, 2.08, 1.01 Hz, 1 H) 8.36 (t, J=1.89 Hz, 1 H) 8.65 (s, 1 H) 11.21 (s, 1 H).

MS, ES ⁺ m/z 485 (M+H) ⁺

Method B

Step 1: Methyl 6-chloro-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxylate

To a solution of methyl 3,6-dichloropyridazine-4-carboxylate (1.5 g, 7.2 mmol) in acetonitrile (15 mL) was added 4-(trifluoromethoxy)phenol (1.4 g, 8.0 mmol) and cesium carbonate. (2.4 g, 7.2 mmol) was added. The resulting mixture was stirred at 40° C. for 1 hour and then diluted with water (100 mL). The mixture was extracted with ethyl acetate (25 mL x 3) and the combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by column chromatography (SiO ₂ , heptane/ethyl acetate, 0-50% gradient) The desired product (1.2 g, 3.4 mmol, 47% yield) was obtained as an oil, which solidified upon standing.

MS, ES ⁺ m/z 349 (M+H) ⁺ Step 2: 6-chloro-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxylic acid

To a solution of methyl 6-chloro-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxylate (1.2 g, 3.4 mmol) in methanol (15 mL) was added water (5 mL) and excess of solid sodium hydroxide was added. The resulting mixture was allowed to stir at room temperature for 1.5 hours and then diluted with water (75 mL). The pH was adjusted to ~1 by carefully adding 6N hydrochloric acid to allow a precipitate to form. The precipitate was collected by filtration, rinsed with water and dried by suction to give the desired product (365 mg, 1.1 mmol, 32% yield) as a colorless solid.

MS, ES ⁺ m/z 335 (M+H) ⁺

Step 3: 6-Chloro-N-(3-(methylsulfonyl)phenyl)-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxamide

6-Chloro-3-(4-(trifluoromethoxy)phenoxy)pyridazine-4-carboxylic acid (365 mg, 1.1 mmol) was dissolved in dichloromethane (5 mL), and oxalyl chloride (0.14 mL, 1.6 mmol) was added, followed by the addition of one drop of N,N-dimethylformamide. The resulting mixture was allowed to stir at room temperature for 1 hour and then cooled in an ice bath. 3-(Methylsulfonyl)aniline (225 mg, 1.3 mmol) and triethylamine (0.15 mL, 1.1 mmol) were added dropwise as a solution in dichloromethane (5 mL) and the mixture was allowed to warm to room temperature. The volatiles were removed under reduced pressure, and the resulting residue was purified by preparative RP-HPLC (water/acetonitrile, 5-95% gradient) to give the desired product (239 mg, 0.49 mmol, 45% yield) as a colorless solid. It was obtained as.

¹ H NMR (400 MHz, DMSO-d ₆ ): d ppm 3.24 (s, 3 H) 7.41 - 7.55 (m, 4 H) 7.65 - 7.78 (m, 2 H) 7.94 (dt, J=7.83, 1.64 Hz , 1 H) 8.31 - 8.39 (m, 2 H) 11.24 (s, 1 H)

MS, ES ⁺ m/z 488 (M+H) ⁺

Compounds of formula (I-IV) could be prepared by the following methodology:

Example 122

Assay method

The ability of the pyridazine carboxamide derivatives exemplified above to inhibit Nav1.8 channels was determined using one or more of the methods described below.

HEK Nav1.8 β1/β2 stably expressing cell line

A HEK293 cell line stably expressing the human Nav1.8 (hNav1.8) ion channel with β1/β2 subunits was constructed. Cell lines are suitable for IC ₅₀ determination in fluorescence and electrophysiology based assays. Electrophysiological assays are also suitable to form mechanism of action pharmacological studies. HEK293 Nav1.8 cells were grown in DMEM/high glucose _medium with selection agents G418 (400 mg/L) and puromycin (0.5 mg/L), 10% fetal bovine serum, Na pyruvate (2 mM) at 37°C, 10% CO 2 ), grown as adherent monolayers in Hepes (10 mM).

Na _v 1.8 fluorescence inhibition assay

Compounds were prepared or supplied as 10 mM stock solutions using DMSO as vehicle. Concentration-response curves were generated using a matrix multichannel pipettor. Compound source plates were prepared by diluting 10mM compound stock solutions to create 500 μM (100x) solutions in DMSO in 96 well v-bottom plates. Compounds were then serially diluted in 100% DMSO to generate a 5-point, 4-fold dilution scheme dose response curve. Then, 2 μl of 100x dose response curve was added to the preincubation and stimulation assay plates. 100 μl of pre-incubation buffer and 200 μl of stimulation buffer were then added to the plate to produce a final assay test concentration range of 5 μM to 0.02 μM with a final DMSO concentration of 1%.

On the day of assay, the plates were washed using 2K EBSS buffer (135mM NaCl, 2mM KCl, 5mM glucose, 2mM CaCl2, 1mM MgCl2, 10mM HEPES, pH 7.4) to remove cell culture medium. The Na-sensitive fluorescent dye Asant Sodium Green-2 (ANG-2) was incubated for 60 minutes to equilibrate and then washed with 2K EBSS. The plate was transferred to a fluorescence plate reader (FLIPR™, Molecular Devices) for fluorescence measurements using an excitation wavelength of 490 nm and an emission wavelength of 565 nm. Compounds were pre-incubated for 5 min at the final test concentration in the presence of ouabain (30 μM) to inhibit Na+ efflux through the Na+/K+ exchanger. After a pre-incubation step, hNav1.8 channels were stimulated with 10 μM of the pyrethroid deltamethrin to prevent channel inactivation. The assay was run for 15 minutes using vehicle and 30 μM tetracaine as negative and positive controls, respectively. The peak change in fluorescence for negative and positive control wells was calculated and fitted to a logistic equation to determine the IC ₅₀ .

PatchXpress Na _v 1.8 inhibition assay

HEK-Nav1.8 β1/β2 cells were recorded in whole-cell patch-clamp using the PatchXPress automated patch clamp platform (Molecular Devices). Cell suspensions were obtained by trypsinization of adherent monolayers followed by gentle shaking for at least 30 minutes. Compounds were prepared from 10 mM DMSO stock solutions.

Nav1.8 channel variants were assessed using Protocol 1 shown in Figure 1, in which cells were initially voltage clamped at a holding potential of -100 mV to maintain Nav1.8 in a closed resting state. After the current amplitude had stabilized, the midpoint voltage of steady-state inactivation was determined for each cell using a series of 5-second conditioning steps with increasing depolarizing voltages (-100 to 0 mV). The holding potential was then reset to a voltage that produced ~50% inactivation (V _half - set automatically via the PatchXpress script), allowing assessment of closure and inactivation channel inhibition. Protocol 1 was run at a frequency of 0.1 Hz until the current amplitude was steady-state (automatically determined by the PatchXpress script). The effect of test reagents on Nav current amplitude was monitored using a custom PatchXpress stability script that determines the timing of compound additions and washouts.

Data were processed and analyzed using DataXpress 2.0 (Molecular Devices). Percent inhibition was calculated using Microsoft Excel, compound block control and wash currents according to the equation, % inhibition = ((Control+Wash)/2)-Drug)/((Control+Wash)/2)*100 Normalize to the average of . The normalized concentration-response relationship was fit using XLfit software (IDBS) 4 parameter logistic model or sigmoidal dose-response model.

hNa _V 1.8 Automated Patch Clamp-Ion Flux ^HT Assay

Inward sodium currents were recorded using the IonFlux HT automated whole-cell patch-clamp instrument (Fluxion Biosciences, Inc., Almeda, CA, USA).

Cells: HEK-293 cells were stably transfected with human Na _V 1.8 cDNA (Type Cells were harvested using trypsin and maintained at room temperature in serum-free medium before recording. Cells were washed, resuspended in extracellular solution, and then applied to the device.

Test concentrations: Stock solutions were prepared at 300X the final assay concentration in DMSO and stored at -80°C until assay date. On the day of the assay, an aliquot of the stock solution was thawed and diluted with external solution to prepare the final test concentration. A final concentration of 0.33% DMSO was maintained for each concentration of test compound and control.

Recording conditions: Intracellular solution (mM): 100 CsF, 45 CsCl, 5 NaCl, 10 HEPES, 5 EGTA (pH 7.3, titrated with 1M CsOH).

Extracellular solution (mM): 150 NaCl, 4 BaCl, 1 MgCl ₂ , 1.8 CaCl ₂ , 10 HEPES, 5 glucose, (pH 7.4, titrated with 10M NaOH).

When a sodium channel is held at a depolarizing membrane potential, the channel opens and becomes inactivated, and remains inactivated until the membrane potential is stepped back to the hyperpolarizing membrane potential when the inactivated channel returns to the closed state. . Compounds that show more inhibition in pulse 2 compared to pulse 1 are state-dependent inhibitors. An example is tetracaine, which is a much more potent inhibitor in the inactivated state than in the tonic or open state.

Cells were held at -120 mV for 50 ms, then stepped to -10 mV for 2 s to completely inactivate the sodium channels (pulse 1), then stepped again to -120 mV for 10 ms (to allow complete recovery from inactivation). , channels with inhibitors bound to them cannot recover from inactivation), and stepped to -10 mV for 50 ms (pulse 2). The sweep interval was 20 s (0.05 Hz). Each concentration of compound was applied for 2 minutes. The assay was performed at room temperature.

Reference compound: Tetracaine was used as a positive control and tested simultaneously with the test compound.

Data analysis: Only current amplitudes exceeding 3 nA in the control phase were analyzed. The amplitude of the sodium current was calculated by measuring the difference between the peak inward current when stepping to -10 mV (i.e., the peak of the current) and the residual current at the end of the step. Sodium currents were assessed in vehicle control conditions and then at the end of each 2 minute compound application. Individual cell trap results were normalized to vehicle control amplitude and mean ± SEM calculated for each compound concentration. These values were then plotted and the estimated IC ₅₀ curve fit was calculated.

Activity of representative Nav1.8 inhibitors

The ability of the representative pyridazine carboxamide derivatives exemplified above to inhibit Nav1.8 channels was determined using one or more of the methods described immediately above.

+ IC ₅₀ > 1 μM

++ IC ₅₀ 500 nM - 1 μM

+++ IC ₅₀ < 500 nM

references

All publications, patent applications, patents, and other references mentioned in the specification are indicative of the level of skill in the art to which the subject matter disclosed herein pertains. All publications, patent applications, patents, and other references are herein incorporated by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. Although numerous patent applications, patents, and other references are mentioned herein, it will be understood that such references are not an admission that any of these documents form part of the common general knowledge in the art.

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VI. Incorporated by reference

References and citations to other literature, such as patents, patent applications, patent publications, journals, books, papers, and web content, are made throughout this disclosure. All such documents are incorporated herein by reference in their entirety for all purposes.

VII. equivalent

In addition to those shown and described herein, various modifications of the invention and many additional embodiments thereof will become apparent to those skilled in the art from the entire contents of this document, including reference to the scientific and patent literature cited herein. will be. The subject matter herein contains important information, examples and instructions that may be adapted to the practice of the invention in its various embodiments and equivalents thereof.

Claims (214)

A compound of formula (II) or a pharmaceutically acceptable salt thereof.

here:
Each of J ₁ , J ₂ , J ₄ , and J ₅ is independently N, NO, or CR ₆ ;
J ₃ is N, NO, or CR ₇ ;
X is CH or N;
Y is NR ₈ or O;
Z is CH, N or NO,
R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;
Each occurrence of R ₆ is independently H, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, CD ₃ or CT ₃ ;
R ₇ is H, halogen, -CD ₃ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, -CF ₃ , -OCF ₃ , each ring has 5 or heterocyclyl having 6 members, heteroaryl having 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, each ring having 5 or 6 members, O-aryl, each O-heteroaryl, O-cycloalkyl, O-cycloheteroalkyl, wherein the ring has 5 or 6 members, each of which is optionally substituted as valence permits;
R ₈ is H, C _1-3 alkyl, or C _3-5 cycloalkyl, acyl,
step,
X and Z cannot both be CH;
Two or less of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO. The compound according to claim 1, wherein Y is NR ₈ . The compound of claim 1, wherein Y is O. The compound of claim 1, wherein R ₂ is alkyl. The compound according to claim 4, wherein R ₂ is -CH ₃ . The compound according to claim 1, wherein none of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ is N or NO. The compound according to claim 1, wherein one of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ is N or NO. The compound according to claim 1, wherein two of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO. The compound of claim 1, wherein Z is CH. The compound according to claim 1, wherein Z is N. A method of treating a condition in a subject, comprising providing the subject with the condition with a compound of formula (II), or a pharmaceutically acceptable salt thereof.

here:
Each of J ₁ , J ₂ , J ₄ , and J ₅ is independently N, NO, or CR ₆ ;
J ₃ is N, NO, or CR ₇ ;
X is CH or N;
Y is NR ₈ or O;
Z is CH, N or NO,
R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;
Each occurrence of R ₆ is independently H, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, CD ₃ or CT ₃ ;
R ₇ is H, halogen, -CD ₃ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, -CF ₃ , -OCF ₃ , each ring has 5 or heterocyclyl having 6 members, heteroaryl having 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, each ring having 5 or 6 members, O-aryl, each O-heteroaryl, O-cycloalkyl, O-cycloheteroalkyl, wherein the ring has 5 or 6 members, each of which is optionally substituted as valence permits;
R ₈ is H, C _1-3 alkyl, or C _3-5 cycloalkyl,
step,
X and Z cannot both be CH;
Two or less of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO. 12. The method of claim 11, wherein Y is NR ₈ . 12. The method of claim 11, wherein Y is O. 12. The method of claim 11, wherein R ₂ is alkyl. 15. The method of claim 14, wherein R ₂ is -CH ₃ . 12. The method of claim 11, wherein none of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ is N or NO. 12. The method of claim 11, wherein one of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ is N or NO. 12. The method of claim 11, wherein two of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO. 12. The method of claim 11, wherein Z is CH. 12. The method of claim 11, wherein Z is N. A compound of formula (III) or a pharmaceutically acceptable salt thereof.

here:
Each of J ₁ , J ₂ , J ₄ , and J ₅ is independently N, NO, or CR ₆ ;
J ₃ is N, NO, or CR ₇ ;
Each W ₁ , W ₂ , W ₃ , W ₄ , and W ₅ is independently N, CH, or CR ₉ ;
X is CH or N;
Z is CH, N or NO,
Each occurrence of R ₆ is independently -H, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, CD ₃ or CT ₃ ;
R ₇ is -H, halogen, -CD ₃ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, -CF ₃ , -OCF ₃ , each ring Carbocyclyl with 3 to 6 members, heterocyclyl with each ring having 5 or 6 members, heteroaryl with 5 or 6 ring members, saturated hetero, with each ring having 3 to 6 members. Cycryl, or partially unsaturated heterocyclyl, O-aryl, each ring having 5 or 6 members, O-heteroaryl, each ring having 5 or 6 members, O-cycloalkyl, O-cyclohetero alkyl, each of which is optionally substituted where valency permits,
R ₉ in each case is independently -C(O)NR ₁₀ R ₁₁ , -S(O) ₂ C _1-6 alkyl, -S(O)(NH)C _1-6 alkyl, C _1-3 alkyl, or C _3-5 cycloalkyl;
Each R ₁₀ and R ₁₁ is independently selected from -H and C _1-5 alkyl, or R ₁₀ and R ₁₁ together with the nitrogen atom to which they are attached form a heterocyclyl having 3-6 members. and wherein each C _1-5 alkyl and heterocyclyl are optionally substituted if valency permits,
step,
Up to two of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO;
At most two of W ₁ , W ₂ , W ₃ , W ₄ and W ₅ are N;
Three or fewer of W ₁ , W ₂ , W ₃ , W ₄ and W ₅ are CR ₉ ;
X and Z cannot both be CH. The method of claim 21, wherein W ₃ CR ₉ phosphorus compound. 23. The compound according to claim 22, wherein R ₉ is -C(O)NH ₂ . The method of claim 21, wherein W ₃ Compound with N. 22. The compound according to claim 21, wherein W ₂ is CH and W ₄ is CR ₉ . 26. The compound according to claim 25, wherein R ₉ is -C(O)NH ₂ . 22. The compound of claim 21, wherein W ₂ and W ₄ are both CR ₉ . 28. The compound of claim 27, wherein W ₂ is CC(O)NH ₂ and W ₄ is CS(O) ₂ CH ₃ . 22. The compound of claim 21, wherein X and Z are both N. The method of claim 21, wherein the formula (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), and A compound selected from the group consisting of (III-8).

Inhibitors of the Na _V 1.8 sodium channel having the structure of formula (III) or a pharmaceutically acceptable salt thereof.

here:
Each of J ₁ , J ₂ , J ₄ , and J ₅ is independently N, NO, or CR ₆ ;
J ₃ is N, NO, or CR ₇ ;
Each W ₁ , W ₂ , W ₃ , W ₄ , and W ₅ is independently N, CH, or CR ₉ ;
X is CH or N;
Z is CH, N or NO,
Each occurrence of R ₆ is independently -H, halogen, C _1-3 alkyl, C _3-5 cycloalkyl, C _1-3 alkoxy, CD ₃ or CT ₃ ;
R ₇ is -H, halogen, -CD ₃ , alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, -CF ₃ , -OCF ₃ , each ring Carbocyclyl with 3 to 6 members, heterocyclyl with each ring having 5 or 6 members, heteroaryl with 5 or 6 ring members, saturated hetero, with each ring having 3 to 6 members. Cycryl, or partially unsaturated heterocyclyl, O-aryl, each ring having 5 or 6 members, O-heteroaryl, each ring having 5 or 6 members, O-cycloalkyl, O-cyclohetero alkyl, each of which is optionally substituted where valency permits,
R ₉ in each case is independently -C(O)NR ₁₀ R ₁₁ , -S(O) ₂ C _1-6 alkyl, -S(O)(NH)C _1-6 alkyl, C _1-3 alkyl, or C _3-5 cycloalkyl;
Each R ₁₀ and R ₁₁ is independently selected from -H and C _1-5 alkyl, or R ₁₀ and R ₁₁ together with the nitrogen atom to which they are attached form a heterocyclyl having 3-6 members. and wherein each C _1-5 alkyl and heterocyclyl are optionally substituted if valency permits,
step,
Up to two of J ₁ , J ₂ , J ₃ , J ₄ and J ₅ are N or NO;
At most two of W ₁ , W ₂ , W ₃ , W ₄ and W ₅ are N;
Three or fewer of W ₁ , W ₂ , W ₃ , W ₄ and W ₅ are CR ₉ ;
X and Z cannot both be CH. The method of claim 31, wherein W ₃ CR ₉ phosphorus inhibitor. 33. The inhibitor of claim 32, wherein R ₉ is -C(O)NH ₂ . The method of claim 31, wherein W ₃ N-phosphorus inhibitor. 32. The inhibitor of claim 31, wherein W ₂ is CH and W ₄ is CR ₉ . 36. The compound of claim 35, wherein R ₉ is -C(O)NH ₂ . 32. The inhibitor of claim 31, wherein W ₂ and W ₄ are both CR ₉ . 38. The inhibitor of claim 37, wherein W ₂ is CC(O)NH ₂ and W ₄ is CS(O) ₂ CH ₃ . 32. The inhibitor of claim 31, wherein X and Z are both N. 32. The method of claim 31, wherein the formulas (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), and An inhibitor represented by a structure selected from the group consisting of (III-8).

A compound of formula (I) or a pharmaceutically acceptable salt thereof.

here:
R ₁ is -CN or -CF ₃ ;
R ₃ is halogen, alkyl, alkoxy or -CD ₃ ;
R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring having 5 or 6 members. a fused heterocyclyl, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;
E is CH or CF;
X is CH or N;
Z is CH or N;
-CD ₃ is It is a fully deuterated methyl group,
However, both X and Z cannot be CH. The method of claim 41, wherein R ₁ Compounds that are -CN. The method of claim 42, wherein R ₁ -CF ₃ phosphorus compound. The method of claim 41, wherein R ₃ A compound that is a halogen. The method of claim 41, wherein R ₃ Alkyl compounds. The method of claim 41, wherein R ₃ Alkoxylic compounds. 42. The compound of claim 41, wherein E is CH. 42. The compound of claim 41, wherein E is CF. 42. The compound of claim 41, wherein Z is CH. 42. The compound of claim 41, wherein Z is N. A method of treating a condition in a subject, comprising providing the subject with the condition with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

here:
R ₁ is -CN or -CF ₃ ;
R ₃ is halogen, alkyl, alkoxy or -CD ₃ ;
R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring having 5 or 6 members. a fused heterocyclyl, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;
E is CH or CF;
X is CH or N;
Z is CH or N;
-CD ₃ is It is a fully deuterated methyl group,
However, both X and Z cannot be CH. The method of claim 51, wherein R ₁ -How to be CN. The method of claim 52, wherein R ₁ -How to be CF ₃ . The method of claim 51, wherein R ₃ How to be halogen. The method of claim 51, wherein R ₃ Alkyl method. The method of claim 51, wherein R ₃ Alkoxy method. 52. The method of claim 51, wherein E is CH. 52. The method of claim 51, wherein E is CF. 52. The method of claim 51, wherein Z is CH. 52. The method of claim 51, wherein Z is N. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

here:
R ₁ is halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;
R ₂ is selected from the group consisting of aryl, heteroaryl and unsaturated heterocyclyl, where:
Each aryl, heteroaryl and unsaturated heterocyclyl is optionally saturated carbocyclyl containing 5-6 ring members and optionally saturated heterocyclyl containing 5-6 ring members and 1-3 heteroatoms. randomly fused to one selected from the group consisting of;
Each aryl, heteroaryl and unsaturated heterocyclyl is -(CH ₂ ) _n NR ^e C(O)N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ , -(CH ₂ ) _n NR ^e C(O)NR ^e R ^j , -(CH ₂ ) _n NR ^e C(O)OR ^j , -(CH ₂ ) _n NR ^e C(O)R ^j , -(CH ₂ ) _n NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ , -( CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m R ^j , alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl Ponyl, alkyl sulfoxide, alkyl sulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, -C(O)NH ₂ , -C(O)NR ^e R ^j , -C(O)R ^j , C ₁ -C ₄ alkoxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ cycloheteroalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -CN, -CO ₂ H, -CO ₂ R ^j , cyano, -H, halogen, heteroaryl, mono-, di- and trihalo-C ₁ -C ₄ Alkyl, mono-, di- or trihaloalkoxyl, morpholinyl, nitro, O-aryl, -OC(O)N(R ^j ) ₂ , -OC(O)NR ^e R ^j , -OC(O) R ^j , -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ cycloheteroalkyl, -OC ₃ -C ₆ cycloalkyl, -OH, O-heteroaryl, oxazolyl, Oxo, -S(O) ₂ R ^j , -SO ₂ aryl, -SO ₂ C ₁ -C ₆ alkenyl, -SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₂ -C ₆ cycloheteroalkyl, - SO ₂ C ₃ -C ₆ cycloalkyl, SO ₂ heteroaryl, -SO ₂ NH ₂ , -SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ alkyl, -SO ₂ NR ^e C ₂ - C ₆ alkenyl, -SO ₂ NR ^e C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H, -SR ^j , Sulfoximinyl -S(O)(=NR ^a )R ^a , Sulfonimidamide -S(O)(=NR ^a )N(R ^a ) ₂ , Sulfonimidoyl fluoride -S(O)(=NR ^a ) F and sulfondiimine -S (=NR ^a ) ₂ R ^a , wherein each of the alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl substituents is itself optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl) and -N(C ₁ -C ₆ alkyl) ₂ ;
unsaturated heterocyclyl is optionally substituted with R ^k R ^l ;
Each heteroatom in heteroaryl, unsaturated heterocyclyl, and optionally saturated heterocyclyl is independently O, S, or N(R ^h ) _q , each of which may be in its oxidized or non-oxidized state;
R ₃ is -H, cyano, halogen, C ₁ -C ₄ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ -C ₄ alkoxyl, optionally substituted C ₁ -C ₈ alkyl, and C ₃ -C ₈ cycloalkyl optionally substituted with 1-4 fluorine atoms;
Each R ^a is independently halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;
each R ^e is independently -H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl;
Each R ^h is independently -H, or C ₁ -C ₆ alkyl;
Each R ^j is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ cycloheteroalkyl, aryl, or ^heteroaryl , wherein Each of the alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, cyano, and -S(O) ₂ CH ₃ ;
R ^k and R ^l are Together with the atoms to which they are attached, they form a cycloalkyl or cycloheteroalkyl containing 3 to 7 ring members;
E is CH, CF or N;
Q is CH, CF or N;
T is CH, CF or N;
W is CH, CF or N;
X is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,
Y is N or N ⁺ O ^- ;
Z is N, N ⁺ O ^- or CH;
Each m is independently 0-2;
Each n is independently 0-4;
Each q is independently 0 or 1. 62. The compound of claim 61, wherein R ₂ is optionally substituted aryl. 62. The compound of claim 61, wherein R ₂ is optionally substituted heteroaryl. 62. The compound of claim 61, wherein R ₂ is optionally substituted unsaturated heterocyclyl. 62. The compound of claim 61, wherein R ₁ is halogen. 62. The compound of claim 61, wherein R ₁ is C ₁ -C ₃ alkyl. 62. The compound of claim 61, wherein R ₁ is C ₃ -C ₄ cycloalkyl. 62. The compound of claim 61, wherein R ₁ is haloalkyl. 62. The compound of claim 61, wherein R ₁ is halocycloalkyl. 62. The compound of claim 61, wherein R ₁ is H. 62. The compound of claim 61, wherein R ₃ is mono-, di- or trihalo-C ₁ -C ₄ alkyl. 62. The compound of claim 61, wherein R ₃ is -CF ₃ . 62. The compound of claim 61, wherein E is CH or CF. 62. The compound of claim 61, wherein E is N. 62. The compound of claim 61, wherein Q is CH or CF. 62. The compound of claim 61, wherein Q is N. 62. The compound of claim 61, wherein T is CH or CF. 62. The compound of claim 61, wherein T is N. 62. The compound of claim 61, wherein W is CH or CF. 62. The compound of claim 61, wherein W is N. A method of treating a condition in a subject, comprising providing the subject with the condition with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

here:
R ₁ is halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;
R ₂ is selected from the group consisting of aryl, heteroaryl and unsaturated heterocyclyl, where:
Each aryl, heteroaryl and unsaturated heterocyclyl is substituted into an optionally saturated carbocyclyl containing 5-6 ring members and an optionally saturated heterocyclyl containing 5-6 ring members and 1-3 heteroatoms. randomly fused to one selected from the group consisting of;
Each aryl, heteroaryl and unsaturated heterocyclyl is -(CH ₂ ) _n NR ^e C(O)N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e C(O)N(R ^j ) ₂ , -(CH ₂ ) _n NR ^e C(O)NR ^e R ^j , -(CH ₂ ) _n NR ^e C(O)OR ^j , -(CH ₂ ) _n NR ^e C(O)R ^j , -(CH ₂ ) _n NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ , -( CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m R ^j , alkyliminosulfanonyl, alkylsulfinyl, alkylsulfonamidyl, alkylsulfonyl Ponyl, alkyl sulfoxide, alkyl sulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, -C(O)NH ₂ , -C(O)NR ^e R ^j , -C(O)R ^j , C ₁ -C ₄ alkoxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ cycloheteroalkyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -CN, -CO ₂ H, -CO ₂ R ^j , cyano, -H, halogen, heteroaryl, mono-, di- and trihalo-C ₁ -C ₄ Alkyl, mono-, di- or trihaloalkoxyl, morpholinyl, nitro, O-aryl, -OC(O)N(R ^j ) ₂ , -OC(O)NR ^e R ^j , -OC(O) R ^j , -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ cycloheteroalkyl, -OC ₃ -C ₆ cycloalkyl, -OH, O-heteroaryl, oxazolyl, Oxo, -S(O) ₂ R ^j , -SO ₂ aryl, -SO ₂ C ₁ -C ₆ alkenyl, -SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₂ -C ₆ cycloheteroalkyl, - SO ₂ C ₃ -C ₆ cycloalkyl, SO ₂ heteroaryl, -SO ₂ NH ₂ , -SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ alkyl, -SO ₂ NR ^e C(O)C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ alkyl, -SO ₂ NR ^e C ₂ - C ₆ alkenyl, -SO ₂ NR ^e C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H, -SR ^j , Sulfoximinyl -S(O)(=NR ^a )R ^a , Sulfonimidamide -S(O)(=NR ^a )N(R ^a ) ₂ , Sulfonimidoyl fluoride -S(O)(=NR ^a ) F and sulfondiimine -S (=NR ^a ) ₂ R ^a , wherein each of the alkenyl, alkyl, aryl, cycloalkyl, cycloheteroalkyl and heteroaryl substituents is itself optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl) and -N(C ₁ -C ₆ alkyl) ₂ ;
unsaturated heterocyclyl is optionally substituted with R ^k R ^l ;
Each heteroatom in heteroaryl, unsaturated heterocyclyl, and optionally saturated heterocyclyl is independently O, S, or N(R ^h ) _q , each of which may be in its oxidized or non-oxidized state;
R ₃ is -H, cyano, halogen, C ₁ -C ₄ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ -C ₄ alkoxyl, optionally substituted C ₁ -C ₈ alkyl, and C ₃ -C ₈ cycloalkyl optionally substituted with 1-4 fluorine atoms;
Each R ^a is independently halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;
each R ^e is independently -H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl;
Each R ^h is independently -H, or C ₁ -C ₆ alkyl;
Each R ^j is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ cycloheteroalkyl, aryl, or ^heteroaryl , wherein Each of the alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, cyano, and -S(O) ₂ CH ₃ ;
R ^k and R ^l are Together with the atoms to which they are attached, they form a cycloalkyl or cycloheteroalkyl containing 3 to 7 ring members;
E is CH or CF;
Q is CH, CF or N;
T is CH, CF or N;
W is CH, CF or N;
X is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,
Y is N or N ⁺ O ^- ;
Z is N or N ⁺ O ^- ,
Each m is independently 0-2;
Each n is independently 0-4;
Each q is independently 0 or 1. 82. The method of claim 81, wherein R ₂ is optionally substituted aryl. 82. The method of claim 81, wherein R ₂ is optionally substituted heteroaryl. 82. The method of claim 81, wherein R ₂ is optionally substituted unsaturated heterocyclyl. 81. The method of claim 81, wherein R ₁ How to be halogen. 81. The method of claim 81, wherein R ₁ C ₁ -C ₃ alkyl method. 81. The method of claim 81, wherein R ₁ C ₃ -C ₄ cycloalkyl. 81. The method of claim 81, wherein R ₁ How to be a haloalkyl. 81. The method of claim 81, wherein R ₁ Halocycloalkyl method. 81. The method of claim 81, wherein R ₁ How to H. 81. The method of claim 81, wherein R ₃ mono-, di- or trihalo-C ₁ -C ₄ alkyl. 81. The method of claim 81, wherein R ₃ -How to be CF ₃ . 82. The method of claim 81, wherein E is CH or CF. 82. The method of claim 81, wherein E is N. 82. The method of claim 81, wherein Q is CH or CF. 82. The method of claim 81, wherein Q is N. 82. The method of claim 81, wherein T is CH or CF. 82. The method of claim 81, wherein T is N. 82. The method of claim 81, wherein W is CH or CF. 82. The method of claim 81, wherein W is N. 82. The method of claim 81, wherein the condition is abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute pruritus, acute pain, acute pain from major trauma/injury, airway hyperresponsiveness, allergic dermatitis, allergy, ankylosing spondylitis, asthma, Atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy- Causes peripheral neuropathy, cholestasis, chronic cough, chronic itching, chronic back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndrome, and additional attacks. Accompanying persistent unilateral facial pain, contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, Epilepsy, extremity pain, Fabry disease, facet joint syndrome, failed spinal surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary Red pain, irritable bowel syndrome, irritable bowel syndrome, pruritus, juvenile idiopathic arthritis, mastocytosis, adenoid hyperostosis, migraine, multiple sclerosis, musculoskeletal injury, myofascial orofacial pain, post-ischemic neurodegeneration, type II neurofibromatosis, nerve Pathogenic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, congenital onychohypertrophy, pain, pain due to cancer. , pain due to chemotherapy, pain due to diabetes, pain syndrome, painful joint arthroplasty, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain. Pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, post-operative pain, post-stroke pain, post-operative pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, pre-operative pain, pruritus, psoriasis. , psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, From the group consisting of small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, short pain, subacute cough, temporomandibular joint disorder, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, and whiplash-related disorders. How to be chosen. The method of claim 101, wherein the condition is abdominal cancer pain, acute idiopathic transverse myelitis, acute pain, acute pain from major trauma/injury, ankylosing spondylitis, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burning mouth syndrome. , calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, chronic back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic diffuse pain. , cluster headaches, complex regional pain syndrome, persistent unilateral facial pain with additional attacks, toothache, complex regional pain syndrome, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, Ehlers-Danlos syndrome, Endometriosis, epidermolysis bullosa, erythroderma, Fabry disease, facet joint syndrome, failed spinal surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel. Disease, inflammatory pain, irritable bowel syndrome, juvenile idiopathic arthritis, mastocytosis, adenoid hyperostosis, migraine, multiple sclerosis, myofascial orofacial pain, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic Pain, nociceptive pain, non-cardiac chest pain, oral mucosal pain, orofacial pain, osteoarthritis, congenital onychohypertrophy, pain, pain due to cancer, pain due to chemotherapy, pain due to diabetes, pain syndrome, painful joint arthroplasty , Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, Post-operative pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, pre-operative pain, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, rheumatoid arthritis, salivary gland pain, Sarcoidosis, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, brachydactyly, temporomandibular joint disorder, tension-type headache, vascular leg ulcer, vulvodynia, and whiplash-related disorders. A method selected from the group consisting of: 102. The method of claim 101, wherein the condition is selected from the group consisting of acute pruritus, allergic dermatitis, chronic pruritus, contact dermatitis, pruritus, and pruritus. 102. The method of claim 101, wherein the condition is selected from the group consisting of acute cough, chronic cough, cough, and subacute cough. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

here:
R ₁ is halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;
R ₂ is cycloalkyl containing 4-6 ring members, cycloheteroalkyl containing 5-6 ring members, spirocycloalkyl containing 5-14 ring members, and 5-14 ring members. is selected from the group consisting of spirocycloheteroalkyl, where
Each cycloalkyl, cycloheteroalkyl, spirocycloalkyl and spirocycloheteroalkyl is an optionally saturated carbocyclyl containing 5-6 ring members and 1-3 heteroatoms. optionally fused to one selected from the group consisting of saturated heterocyclyl;
Each cycloalkyl, cycloheteroalkyl, spirocycloalkyl and spirocycloheteroalkyl is -(CH ₂ ) _n NR ^e C(O)N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e C(O)N (R ^j ) ₂ , -(CH ₂ ) _n NR ^e C(O)NR ^e R ^j , -(CH ₂ ) _n NR ^e C(O)OR ^j , -(CH ₂ ) _n NR ^e C(O) R ^j , -(CH ₂ ) _n NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m R ^j , alkyliminosulfanonyl, alkylsulfinyl, alkyl Sulfonamidyl, alkylsulfonyl, alkylsulfoxide, alkylsulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, -C(O)NH ₂ , -C(O)NR ^e R ^j , - C(O)R ^j , C ₁ -C ₄ alkoxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ cycloheteroalkyl, C ₃ -C ₁₀ Cycloalkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -CN, -CO ₂ H, -CO ₂ R ^j , cyano, -H, halogen, heteroaryl, mono-, di- and trihalo -C ₁ -C ₄ alkyl, mono-, di- or trihaloalkoxyl, morpholinyl, nitro, O-aryl, -OC(O)N(R ^j ) ₂ , -OC(O)NR ^e R ^j , -OC(O)R ^j , -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ cycloheteroalkyl, -OC ₃ -C ₆ cycloalkyl, -OH, O- Heteroaryl, oxazolyl, oxo, -S(O) ₂ R ^j , -SO ₂ aryl, -SO ₂ C ₁ -C ₆ alkenyl, -SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₂ -C ₆ cycloheteroalkyl, -SO ₂ C ₃ -C ₆ cycloalkyl, SO ₂ heteroaryl, -SO ₂ NH ₂ , -SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ alkyl , -SO ₂ NR ^e C(O)C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ alkyl, -SO ₂ NR ^e C ₂ -C ₆ alkenyl, -SO ₂ NR ^e C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H, -SR ^j , sulfoximinyl -S(O)(=NR ^a )R ^a , sulfonimidamide -S(O)(=NR ^a )N(R ^a ) ₂ , sulfonimidoyl fluoride -S (O)(=NR ^a )F, sulfondiimine -S(=NR ^a ) ₂ R ^a , and R ^k R ^l , wherein each of alkenyl, alkyl, Aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituents are themselves halogens, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl), and -N(C ₁ -C ₆ alkyl) _{2 .} is optionally substituted with one or more substituents selected from the group;
Each heteroatom in cycloheteroalkyl, spirocycloheteroalkyl and optionally saturated heterocyclyl is independently O, S or N(R ^h ) _q , each of which may be in its oxidized or non-oxidized state;
R ₃ is -H, cyano, halogen, C ₁ -C ₄ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ -C ₄ alkoxyl, optionally substituted C ₁ -C ₈ alkyl, and C ₃ -C ₈ cycloalkyl optionally substituted with 1-4 fluorine atoms;
Each R ^a is independently halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;
each R ^e is independently -H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl;
Each R ^h is independently -H, or C ₁ -C ₆ alkyl;
Each R ^j is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ cycloheteroalkyl, aryl, or ^heteroaryl , wherein Each of the alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, cyano, and -S(O) ₂ CH ₃ ;
R ^k and R ^l are Together with the atoms to which they are attached, they form a cycloalkyl or cycloheteroalkyl containing 3 to 7 ring members;
E is CH or CF;
Q is CH, CF or N;
T is CH, CF or N;
W is CH, CF or N;
X is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,
Y is N or N ⁺ O ^- ;
Z is N or N ⁺ O ^- ,
Each m is independently 0-2;
Each n is independently 0-4;
Each q is independently 0 or 1. 106. The compound of claim 105, wherein R ₂ is optionally substituted cycloalkyl. 106. The compound of claim 105, wherein R ₂ is optionally substituted cycloheteroalkyl. 106. The compound of claim 105, wherein R ₂ is optionally substituted spirocycloalkyl. 106. The compound of claim 105, wherein R ₂ is optionally substituted spirocycloheteroalkyl. 105. The method of claim 105, wherein R ₁ A compound that is a halogen. 105. The method of claim 105, wherein R ₁ Compounds that are C ₁ -C ₃ alkyl. 105. The method of claim 105, wherein R ₁ Compounds that are C ₃ -C ₄ cycloalkyl. 105. The method of claim 105, wherein R ₁ Compounds that are haloalkyl. 105. The method of claim 105, wherein R ₁ Compounds that are halocycloalkyl. 105. The method of claim 105, wherein R ₁ Compound that is H. 105. The method of claim 105, wherein R ₃ -CF ₃ phosphorus compound. 106. The compound of claim 105, wherein E is CH or CF. 106. The compound of claim 105, wherein E is N. 106. The compound of claim 105, wherein Q is CH or CF. 106. The compound of claim 105, wherein Q is N. 106. The compound of claim 105, wherein T is CH or CF. 106. The compound of claim 105, wherein T is N. 106. The compound of claim 105, wherein W is CH or CF. 106. The compound of claim 105, wherein W is N. A method of treating a condition in a subject, comprising providing the subject with the condition with a compound of formula (I), or a pharmaceutically acceptable salt thereof.

here:
R ₁ is halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;
R ₂ is cycloalkyl containing 4-6 ring members, cycloheteroalkyl containing 5-6 ring members, spirocycloalkyl containing 5-14 ring members, and 5-14 ring members. is selected from the group consisting of spirocycloheteroalkyl, where
Each cycloalkyl, cycloheteroalkyl, spirocycloalkyl and spirocycloheteroalkyl is an optionally saturated carbocyclyl containing 5-6 ring members and 1-3 heteroatoms. optionally fused to one selected from the group consisting of saturated heterocyclyl;
Each cycloalkyl, cycloheteroalkyl, spirocycloalkyl and spirocycloheteroalkyl is -(CH ₂ ) _n NR ^e C(O)N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e C(O)N (R ^j ) ₂ , -(CH ₂ ) _n NR ^e C(O)NR ^e R ^j , -(CH ₂ ) _n NR ^e C(O)OR ^j , -(CH ₂ ) _n NR ^e C(O) R ^j , -(CH ₂ ) _n NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m N(R ^e ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m N(R ^j ) ₂ , -(CH ₂ ) _n NR ^e S(O) _m NR ^e R ^j , -(CH ₂ ) _n NR ^e S(O) _m R ^j , alkyliminosulfanonyl, alkylsulfinyl, alkyl Sulfonamidyl, alkylsulfonyl, alkylsulfoxide, alkylsulfoximine, alkylthioether, amino, aryl, arylalkoxyl, aryloxyl, -C(O)NH ₂ , -C(O)NR ^e R ^j , - C(O)R ^j , C ₁ -C ₄ alkoxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ cycloheteroalkyl, C ₃ -C ₁₀ Cycloalkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -CN, -CO ₂ H, -CO ₂ R ^j , cyano, -H, halogen, heteroaryl, mono-, di- and trihalo -C ₁ -C ₄ alkyl, mono-, di- or trihaloalkoxyl, morpholinyl, nitro, O-aryl, -OC(O)N(R ^j ) ₂ , -OC(O)NR ^e R ^j , -OC(O)R ^j , -OC ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ cycloheteroalkyl, -OC ₃ -C ₆ cycloalkyl, -OH, O- Heteroaryl, oxazolyl, oxo, -S(O) ₂ R ^j , -SO ₂ aryl, -SO ₂ C ₁ -C ₆ alkenyl, -SO ₂ C ₁ -C ₆ alkyl, -SO ₂ C ₂ -C ₆ cycloheteroalkyl, -SO ₂ C ₃ -C ₆ cycloalkyl, SO ₂ heteroaryl, -SO ₂ NH ₂ , -SO ₂ NR ^e -aryl, -SO ₂ NR ^e C(O)C ₁ -C ₆ alkyl , -SO ₂ NR ^e C(O)C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C(O)C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e C ₁ -C ₆ alkyl, -SO ₂ NR ^e C ₂ -C ₆ alkenyl, -SO ₂ NR ^e C ₂ -C ₆ cycloheteroalkyl, -SO ₂ NR ^e C ₃ -C ₆ cycloalkyl, -SO ₂ NR ^e -heteroaryl, -SO ₃ H, -SR ^j , sulfoximinyl -S(O)(=NR ^a )R ^a , sulfonimidamide -S(O)(=NR ^a )N(R ^a ) ₂ , sulfonimidoyl fluoride -S (O)(=NR ^a )F, sulfondiimine -S(=NR ^a ) ₂ R ^a , and R ^k R ^l , wherein each of alkenyl, alkyl, Aryl, cycloalkyl, cycloheteroalkyl, and heteroaryl substituents are themselves halogens, -OH, -NH ₂ , -NH(C ₁ -C ₆ alkyl), and -N(C ₁ -C ₆ alkyl) _{2 .} is optionally substituted with one or more substituents selected from the group;
Each heteroatom in cycloheteroalkyl, spirocycloheteroalkyl and optionally saturated heterocyclyl is independently O, S or N(R ^h ) _q , each of which may be in its oxidized or non-oxidized state;
R ₃ is -H, cyano, halogen, C ₁ -C ₄ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ -C ₄ alkoxyl, optionally substituted C ₁ -C ₈ alkyl, and C ₃ -C ₈ cycloalkyl optionally substituted with 1-4 fluorine atoms;
Each R ^a is independently halogen, C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, haloalkyl, halocycloalkyl, or H;
each R ^e is independently -H, C ₁ -C ₆ alkyl, or C ₂ -C ₆ alkenyl;
Each R ^h is independently -H, or C ₁ -C ₆ alkyl;
Each R ^j is independently C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ cycloheteroalkyl, aryl, or ^heteroaryl , wherein Each of the alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, -OH, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, cyano, and -S(O) ₂ CH ₃ ;
R ^k and R ^l are Together with the atoms to which they are attached, they form a cycloalkyl or cycloheteroalkyl containing 3 to 7 ring members;
E is CH or CF;
Q is CH, CF or N;
T is CH, CF or N;
W is CH, CF or N;
X is halogen, alkyl, haloalkyl, cycloalkyl or halocycloalkyl,
Y is N or N ⁺ O ^- ;
Z is N or N ⁺ O ^- ,
Each m is independently 0-2;
Each n is independently 0-4;
Each q is independently 0 or 1. 126. The method of claim 125, wherein R ₂ is optionally substituted cycloalkyl. 126. The method of claim 125, wherein R ₂ is optionally substituted cycloheteroalkyl. 126. The method of claim 125, wherein R ₂ is optionally substituted spirocycloalkyl. 126. The method of claim 125, wherein R ₂ is optionally substituted spirocycloheteroalkyl. 125. The method of claim 125, wherein R ₁ How to be halogen. 125. The method of claim 125, wherein R ₁ C ₁ -C ₃ alkyl method. 125. The method of claim 125, wherein R ₁ C ₃ -C ₄ cycloalkyl. 125. The method of claim 125, wherein R ₁ How to be a haloalkyl. 125. The method of claim 125, wherein R ₁ Halocycloalkyl method. 125. The method of claim 125, wherein R ₁ How to H. 125. The method of claim 125, wherein R ₃ -How to be CF ₃ . 125. The method of claim 125, wherein E is CH or CF. 126. The method of claim 125, wherein E is N. 125. The method of claim 125, wherein Q is CH or CF. 126. The method of claim 125, wherein Q is N. 125. The method of claim 125, wherein T is CH or CF. 126. The method of claim 125, wherein T is N. 125. The method of claim 125, wherein W is CH or CF. 126. The method of claim 125, wherein W is N. 125. The method of claim 125, wherein the condition is abdominal cancer pain, acute cough, acute idiopathic transverse myelitis, acute pruritus, acute pain, acute pain from major trauma/injury, airway hyperresponsiveness, allergic dermatitis, allergy, ankylosing spondylitis, asthma, Atopy, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burn injury, burning mouth syndrome, calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy- Causes peripheral neuropathy, cholestasis, chronic cough, chronic itching, chronic back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic widespread pain, cluster headache, complex regional pain syndrome, complex regional pain syndrome, and additional attacks. Accompanying persistent unilateral facial pain, contact dermatitis, cough, toothache, diabetic neuropathy, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, Ehlers-Danlos syndrome, endometriosis, epidermolysis bullosa, Epilepsy, extremity pain, Fabry disease, facet joint syndrome, failed spinal surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel disease, inflammatory pain, hereditary Red pain, irritable bowel syndrome, irritable bowel syndrome, pruritus, juvenile idiopathic arthritis, mastocytosis, adenoid hyperostosis, migraine, multiple sclerosis, musculoskeletal injury, myofascial orofacial pain, post-ischemic neurodegeneration, type II neurofibromatosis, nerve Pathogenic ocular pain, neuropathic pain, neuropathic pain, nociceptive pain, non-cardiac chest pain, optic neuritis, oral mucosal pain, orofacial pain, osteoarthritis, osteoarthritis, overactive bladder, congenital onychohypertrophy, pain, pain due to cancer. , pain due to chemotherapy, pain due to diabetes, pain syndrome, painful joint arthroplasty, pancreatitis, Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, peripheral neuropathy, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain. Pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, postherpetic neuralgia, post-mastectomy pain syndrome, post-operative pain, post-stroke pain, post-operative pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, pre-operative pain, pruritus, psoriasis. , psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, renal colic, renal failure, rheumatoid arthritis, salivary gland pain, sarcoidosis, sciatica, scleroderma, sickle cell disease, From the group consisting of small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, short pain, subacute cough, temporomandibular joint disorder, tension-type headache, trigeminal neuralgia, vascular leg ulcers, vulvodynia, and whiplash-related disorders. How to be chosen. The method of claim 145, wherein the condition is abdominal cancer pain, acute idiopathic transverse myelitis, acute pain, acute pain from major trauma/injury, ankylosing spondylitis, Behcet's disease, bladder pain syndrome, bone cancer pain, brachial plexus injury, burning mouth syndrome. , calcium pyrophosphate deposition disease, cervicogenic headache, Charcot neuropathic osteoarthropathy, chemotherapy-induced oral mucositis, chemotherapy-induced peripheral neuropathy, chronic back pain, chronic pain, chronic pancreatitis, chronic post-traumatic headache, chronic diffuse pain. , cluster headaches, complex regional pain syndrome, persistent unilateral facial pain with additional attacks, toothache, complex regional pain syndrome, diabetic peripheral neuropathy, diffuse idiopathic skeletal hyperostosis, disc degeneration pain, Ehlers-Danlos syndrome, Endometriosis, epidermolysis bullosa, erythroderma, Fabry disease, facet joint syndrome, failed spinal surgery syndrome, familial hemiplegic migraine, fibromyalgia, glossopharyngeal neuralgia, glossopharyngeal neuropathic pain, gout, head and neck cancer pain, inflammatory bowel. Disease, inflammatory pain, irritable bowel syndrome, juvenile idiopathic arthritis, mastocytosis, adenoid hyperostosis, migraine, multiple sclerosis, myofascial orofacial pain, neurofibromatosis type II, neuropathic ocular pain, neuropathic pain, neuropathic Pain, nociceptive pain, non-cardiac chest pain, oral mucosa pain, orofacial pain, osteoarthritis, congenital onychohypertrophy, pain, pain due to cancer, pain due to chemotherapy, pain due to diabetes, pain syndrome, painful joint arthroplasty , Parkinson's disease, paroxysmal extreme pain disorder, pemphigus, perioperative pain, persistent idiopathic dentoalveolar pain, persistent idiopathic facial pain, phantom limb pain, phantom limb pain, polymyalgia rheumatica, post-mastectomy pain syndrome, postoperative pain, post-stroke pain, Post-operative pain, post-thoracotomy pain syndrome, post-traumatic stress disorder, pre-operative pain, psoriasis, psoriatic arthritis, pudendal neuralgia, pyoderma gangrenosum, radiotherapy-induced peripheral neuropathy, Raynaud's disease, renal colic, rheumatoid arthritis, salivary gland pain, Sarcoidosis, scleroderma, sickle cell disease, small fiber neuropathy, spinal cord injury pain, spondylolisthesis, spontaneous pain, brachydactyly, temporomandibular joint disorder, tension-type headache, vascular leg ulcer, vulvodynia, and whiplash-related disorders. A method selected from the group consisting of: 146. The method of claim 145, wherein the condition is selected from the group consisting of acute pruritus, allergic dermatitis, chronic pruritus, contact dermatitis, pruritus, and pruritus. 146. The method of claim 145, wherein the condition is selected from the group consisting of acute cough, chronic cough, cough, and subacute cough. Compounds of formula (I) and pharmaceutically acceptable salts thereof.

here:
R ₁ is aryl or heteroaryl, wherein aryl or heteroaryl is unsubstituted or mono-, di-, and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di-, or trihaloalkoxyl, sulfanyl, trifluoro is substituted with one or more groups selected from the group consisting of methylsulfanyl, and arylalkoxyl;
R ₂ is selected from the group consisting of aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted. C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloal. is substituted with one or more groups selected from the group consisting of coxyl, arylalkoxyl, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfanonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;
R ₃ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ ;
R ₄ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or
R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached. According to clause 149,
R ₁ is phenyl or pyridinyl, where phenyl or pyridinyl is unsubstituted, or substituted or unsubstituted C ₁ -C ₈ alkyl, halogen, -OR ₅ (where R ₅ is C ₁ -C ₈ alkyl, - CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8) , and -S-CF ₃ is substituted with one or more groups selected from the group consisting of;
R ₂ is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, and 1,3- selected from the group consisting of benzothiazolyl, wherein phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl, and 1,3-benzothiazolyl is unsubstituted, or unsubstituted or substituted C ₁ -C ₈ alkyl, halogen, cyano, oxo, -OR ₅ (where R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , and -CHF ₂ ), -(CH ₂ ) _q -OH (where q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8), - NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, -C(=O)-R ₈ (where R ₈ is -NR ₆ R ₇ (wherein R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkyl), -S(=O)-R ₉ , -S(=O) ₂ -R ₉ , -S(=O)(=NR ₁₀ )-R ₁₁ , and -N=S(=O)-(R ₁₁ ) ₂ with one or more groups selected from the group consisting of substituted, wherein each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ , or -NR ₆ R ₇ , wherein R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl. and R ₁₀ is H or C ₁ -C ₄ alkyl, R ₁₁ is C ₁ -C ₄ alkyl, provided that when Y is nitrogen and R ₂ is phenyl or pyridyl, R ₈ is -NR ₆ cannot be R ₇ ;
R ₃ is hydrogen, cyano, halogen, -CF ₃ , C ₁ -C ₈ alkoxyl, -O-CH(F) ₂ , substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl , -N ⁺ (=O)-O ^- is selected from the group consisting of;
R ₄ is selected from the group consisting of hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, -CF ₃ , substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ is simultaneously not hydrogen; or
R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached.
compound. 150. The compound of claim 149, which is a compound of formula (II).

here:
R ₂ is selected from the group consisting of aryl, heteroaryl and heterocycle, wherein aryl, heteroaryl and heterocycle are unsubstituted or mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted. C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloal. substituted with one or more groups selected from the group consisting of coxyl, arylalkoxyl, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfanonyl, alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl;
R ₃ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₈ cycloalkyl, -NO ₂ ;
R ₄ is hydrogen, cyano, halogen, C ₁ -C ₈ alkoxyl, mono-, di-, and trihalo-C ₁ -C ₄ alkyl, mono-, di-, and trihalo-C ₁ - selected from the group consisting of C ₄ alkoxyl, substituted or unsubstituted C ₁ -C ₈ alkyl, and morpholinyl, provided that R ₃ and R ₄ are not hydrogen at the same time; or
R ₃ and R ₄ together form a C ₃ -C ₅ carbocyclic ring comprising the carbon atom to which R ₃ and R ₄ are attached;
n is an integer selected from 0, 1, 2, 3, 4 and 5;
Each R ₂₄ is independently mono-, di- and trihalo-C ₁ -C ₄ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₃ -C ₁₀ cycloalkyl, halogen, heteroaryl, cyanoalkyl. selected from the group consisting of gno, amino, nitro, aryloxyl, aryl, C ₁ -C ₈ alkoxyl, mono-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl. According to clause 151,
R ₂ is selected from the group consisting of

here:
m is an integer selected from the group consisting of 0, 1, 2, 3 and 4;
R ₂₅ is H, morpholinyl, oxazolyl, halogen, cyano, -(CH ₂ ) _q -OH (where q is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8) is an integer), -C(=O)-R ₈ where R ₈ is selected from the group consisting of -NR ₆ R ₇ and C ₁ -C ₄ alkyl, where R ₆ and R ₇ are H and C ₁ -C ₄ selected from the group consisting of alkyl), -S(=O)-R ₉ , -S(=O) ₂ -R ₉ , -S(=O)(=NR ₁₀ )-R ₁₁ , and -N=S( =O)-(R ₁₁ ) ₂ (wherein each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ , or -NR ₆ R ₇ , where R ₆ and R ₇ are is selected from the group consisting of H and C ₁ -C ₄ alkyl, R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is C ₁ -C ₄ alkyl, provided that Y is nitrogen and R ₂ is phenyl or In the case of pyridyl, R ₈ is -NR ₆ cannot be R ₇ );
R ₂₆ is halogen or cyano;
each R ₂₇ is independently selected from the group consisting of H, halogen, C ₁ -C ₈ alkoxyl, cyano, and -NR ₆ R ₇ ;
Each R ₂₈ is independently H or C ₁ -C ₄ alkyl
compound. 152. The compound of claim 151, which is a compound of formula (II-a).

here:
R ₂ is selected from the group consisting of aryl and heteroaryl, wherein aryl or heteroaryl is unsubstituted or substituted C ₁ -C ₈ alkyl, halogen, cyano, oxo, heterocycloalkyl, -OR ₅ (where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CH ₂ F, and -CHF ₂ ), -(CH ₂ ) _q -OH (where q is 1, 2, 3, 4, 5, is an integer selected from the group consisting of 6, 7, and 8), -NR ₆ R ₇ where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), morpholinyl, oxazolyl, - C(=O)-R ₈ (where R ₈ is -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl), and C ₁ -C ₄ alkyl) selected from the group), -S(=O)-R ₉ , -S(=O) ₂ -R ₉ , -S(=O)(=NR ₁₀ )-R ₁₁ , and -N=S(=O) -(R ₁₁ ) ₂ (wherein each R ₉ is independently C ₁ -C ₄ alkyl, -CF ₃ , or -NR ₆ R ₇ , where R ₆ and R ₇ are H and C ₁ -C ₄ alkyl) is selected from the group consisting of, R ₁₀ is H or C ₁ -C ₄ alkyl, and R ₁₁ is is optionally substituted with a substituent selected from the group consisting of C ₁ -C ₄ alkyl;
R ₁₂ is selected from the group consisting of halogen, -OR ₂₃ , where R ₂₃ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CH ₂ F, and -CHF ₂ ;
R _12' is selected from the group consisting of H, halogen, -OR ₁₃ , where R ₁₃ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CH ₂ F, and -CHF ₂ . 154. The compound of claim 153, wherein aryl and heteroaryl are selected from the group consisting of phenyl, benzothiazolyl, pyridyl, pyridyl N-oxide, pyridazinyl, and pyrimidinyl. According to clause 154,
R ₂ is (trifluorosulfonyl)phenyl, 1,2,4-triazolyl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-6-yl, 2-fluoro- 5-methylsulfonylphenyl, 2-methoxy-4-pyridyl, 2-methyl-4-pyridyl, 3-(dimethylsulfamoyl)phenyl, 3-(methylsulfonimidoyl)phenyl, 3-(N, S-dimethylsulfonimidoyl)phenyl, 3-carbamoylphenyl, 3-cyanophenyl, 3-dimethylsulfamoylphenyl, 3-methylsulfinylphenyl, 3-methylsulfonylphenyl, 3-morpholinophenyl, 3-oxazol-5-ylphenyl, 3-pyridyl, 4-cyanophenyl, 4-pyridyl, 6-cyano-3-pyridyl, 6-methyl-3-pyridyl, dimethyl (oxo)- λ6-sulfanylidene] amino] phenyl, phenyl, pyrazolyl, pyridazin-4-yl, pyridazinyl, pyridizin-4-yl, pyridyl, pyrimidin-4-yl, pyrimidinyl, and thiadia A compound selected from the group consisting of zolyl. 150. The compound of claim 149, which is a compound of formula (III).

here:
R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, wherein phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;
R ₂ is

is selected from the group consisting of;
R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ . 157. The compound of claim 156, which is a compound of formula (III-a).

here:
R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, wherein phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;
R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ . 157. The method of claim 157, wherein R ₁ A compound selected from the group consisting of 2,4-dichlorophenyl, 4-difluoromethoxyphenyl and 2-chloro-4-methoxyphenyl. 157. The compound of claim 156, which is a compound of formula (III-b).

here:
R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;
R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ . 157. The compound of claim 156, which is a compound of formula (III-c).

here:
R ₁ is one or more of halogen, C ₁ -C ₈ alkyl, phenyl substituted with -OR ₅ , where R ₅ is C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) is selected from the group consisting of _p -CF ₃ , where p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. 160. The method of claim 160, wherein R ₁ 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,4-difluor A compound selected from the group consisting of lophenyl and 3,4-difluorophenyl. 157. The compound of claim 156, which is a compound of formula (III-d).

here:
R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, wherein phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;
R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ . 163. The compound of claim 162, which is a compound of formula (III-d').

here
R ₁ is a group consisting of 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl is selected from 157. The compound of claim 156, which is a compound of formula (III-e).

here:
R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, wherein phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;
R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ . 165. The compound of claim 164, which is a compound of formula (III-e').

here
R ₁ is a group consisting of 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl is selected from 157. The compound of claim 156, which is a compound of formula (III-f).

here:
R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, where phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;
R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ . 167. The compound of claim 166, which is a compound of formula (III-f').

here:
R ₁ is 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl, 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2- It is selected from the group consisting of chloro-4-methoxylphenyl, 3,4-difluorophenyl and 2-chloro-4-fluorophenyl. 157. The compound of claim 156, which is a compound of formula (III-g).

here:
R ₁ is wherein R _2c is selected from the group consisting of H, C ₁ -C ₄ alkyl, halogen, and C ₁ -C ₄ alkoxyl; R _4c is selected from the group consisting of -OCF ₃ , C ₁ -C ₄ alkoxyl, and halogen;
R ₂ is

is selected from the group consisting of According to clause 168,
R ₁

A compound selected from the group consisting of. 169. The compound of claim 168, wherein the compound of formula (III-g) is selected from the group consisting of:
3-(3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide;
3-(3-(2,4-dimethoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide;
3-(3-(2-chloro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridine 1-oxide;
3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-fluoro-2-methoxyphenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(pyridazin-4-yl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-dimethoxyphenoxy)-N-(pyridazin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
5-(3-(2,4-dimethoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide;
5-(3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide;
5-(3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide; and
5-(3-(2-chloro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamido)pyridazine 1-oxide. 150. The compound of claim 149, which is a compound of formula (IV).

here:
R ₂ is selected from the group consisting of:
(i) ; where R _2b is selected from the group consisting of H, C ₁ -C ₄ alkyl, and halogen; R ₁₄ is C ₁ -C ₄ alkyl;
(ii) ; where R _5b is selected from the group consisting of -C(=O)-R ₈ , -(CH ₂ ) _n OH, and cyano, where R ₈ is C ₁ -C ₄ alkyl and n is 1, 2, 3 , is an integer selected from 4, 5, 6, 7 and 8;
(iii) , where R _5b' is selected from the group consisting of H, halogen, and C ₁ -C ₄ alkyl;
(iv) , where R _4b is H or halogen;
(v) , where R ₉ is H or C ₁ -C ₄ alkyl; and
(vi) . 172. The compound of claim 171, which is a compound of formula (IV-a).
According to clause 172,
R ₂

A compound selected from the group consisting of. 173. The compound of claim 172, wherein the compound of formula (IV-a) is selected from the group consisting of:
3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-ethylsulfonylphenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonyl-6-methyl-phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-methylsulfonyl-6-fluoro-phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(3-acetylphenyl)-3-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-[3-(hydroxymethyl)phenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-[3-cyanophenyl]-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(3-pyridyl-N-oxide)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(4-pyridyl-N-oxide)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(2-fluoro-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(2-methyl-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(6-fluoro-3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(6-chloro-3-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(1-methyl-2-oxo-4-pyridyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-Chloro-4-fluoro-phenoxy)-N-(2-oxidopyridazin-2-ium-4-yl)-6-(trifluoromethyl)pyridazine-4-carboxyx amides; and
3-(2-Chloro-4-fluoro-phenoxy)-N-pyrimidin-4-yl-6-(trifluoromethyl)pyridazine-4-carboxamide. 172. The compound of claim 171, which is a compound of formula (IV-b).

here:
R ₁ is selected from the group consisting of phenyl, pyridyl, and 1,3-benzothiazol-4-yl, wherein phenyl and pyridyl are unsubstituted or halogen, C ₁ -C ₈ alkyl, -OR ₅ ( where R ₅ is selected from the group consisting of C ₁ -C ₈ alkyl, -CF ₃ , -CHF ₂ , and -(CH ₂ ) _p -CF ₃ , where p is 1, 2, 3, 4, 5, 6 , 7, and 8), -S-CF ₃ , -NR ₆ R ₇ (where R ₆ and R ₇ are selected from the group consisting of H and C ₁ -C ₄ alkyl). may be replaced with;
R ₃ and R ₄ are H or -CF ₃ provided that R ₃ is In the case of H, R ₄ is -CF ₃ , and if R ₄ is H, R ₃ is -CF ₃ ;
R _2b is selected from the group consisting of H, C ₁ -C ₄ alkyl, and halogen; R ₁₄ is C ₁ -C ₄ alkyl;
R ₁₄ is C ₁ -C ₄ alkyl;
R ₁₅ is O or NR ₁₀ , where R ₁₀ is H or C ₁ -C ₄ alkyl. 175. The method of claim 175, wherein R ₁ Phenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2-propylphenyl, 2-methoxy-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2-isoprop Oxyphenyl, 4-fluoro-2-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, difluoromethoxyphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3-fluorophenyl, 2,5-difluorophenyl, 4-methylphenyl, 3-chloro-5-fluorophenyl, 2-isopropylphenyl, 3, 4-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(trifluoromethylsulphenyl) (panyl)phenyl, 2-dimethylaminophenyl, 2-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl, 6-trifluoromethyl- A compound selected from the group consisting of 3-pyridyl, 1,3-benzothiazol-4-yl, 4-difluoromethoxyphenyl, 2-chloro-4-methoxyphenyl and 2-chlorophenyl. 172. The compound of claim 171, which is a compound of formula (IV-c) and pharmaceutically acceptable salts thereof.

here:
R ₁ is ego; here
R _1a , R _1b , R _1c , R _1d , and R _1e are each independently H, C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F , -OCH ₂ CF ₃ , and -NR ₅ R ₆ , where R ₅ and R ₆ are C ₁ -C ₄ alkyl, provided that R _1a , R _1b , R _1c , R _1d , and R At least one of _1e is not H. The compound of claim 177, wherein:
(i) R _4a is halogen; R _2a is selected from the group consisting of H, C ₁ -C ₄ alkyl, halogen, and C ₁ -C ₄ alkoxyl; R _3a is H or halogen; R _5a is H or halogen; R _6a is H;
(ii) R _2a and R _4a are each C ₁ -C ₄ alkoxyl;
(iii) R _4a is -OF ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(iv) R _4a is -OCHF ₂ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(v) R _4a is -OCH ₂ F; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(vi) R _4a is -OCH ₂ F ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a , R _5a and R _6a are each H;
(vii) R _3a is halogen; R _2a is H or halogen; R _4a and R _5a are H; R _6a is H or halogen; and
(viii) R ₂ is -NR ₅ R ₆ ; R _3a , R _4a , R _5a , and R _6a are each H. In clause 178,
R ₁

A compound selected from the group consisting of. 178. The compound of claim 177, wherein the compound of formula (IV-c) is selected from the group consisting of:
3-(4-fluoro-2-methylphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-dichlorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-dimethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide;
3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl ) Pyridazine-4-carboxamide;
3-(2-fluoro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ;
3-(2-fluoro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ;
3-(2-fluoro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-methyl-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-methyl-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-methyl-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl) Pyridazine-4-carboxamide;
3-(3,4-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(3,4,5-trifluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(3,6-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,3-difluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-3-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(3-fluoro-4-trifluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ;
3-(3-fluoro-4-difluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide ;
3-(3-fluoro-4-fluoromethoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-chloro-2-methoxyphenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and
3-(2-dimethylaminophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. 172. The compound of claim 171, which is a compound of formula (IV-d) and a pharmaceutically acceptable salt thereof.

here:
R ₁ is ego; here
R _1a , R _1b , R _1c , R _1d , and R _1e are each independently H, C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F , -OCH ₂ CF ₃ , and -NR ₅ R ₆ , where R ₅ and R ₆ are C ₁ -C ₄ alkyl, provided that R _1a , R _1b , R _1c , R _1d , and R At least one of _1e is not H. 182. The compound of claim 181, wherein:
(i) R _4a is halogen; R _2a is selected from the group consisting of H, C ₁ -C ₄ alkyl, halogen, and C ₁ -C ₄ alkoxyl; R _3a is H or halogen; R _5a is H or halogen; R _6a is H;
(ii) R _2a and R _4a are each C ₁ -C ₄ alkoxyl;
(iii) R _4a is -OF ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(iv) R _4a is -OCHF ₂ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(v) R _4a is -OCH ₂ F; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(vi) R _4a is -OCH ₂ F ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a , R _5a and R _6a are each H;
(vii) R _3a is halogen; R _2a is H or halogen; R _4a and R _5a are H; R _6a is H or halogen; and
(viii) R ₂ is -NR ₅ R ₆ ; R _3a , R _4a , R _5a , and R _6a are each H. According to clause 182,
R ₁

A compound selected from the group consisting of. 182. The compound of claim 181, wherein the compound of formula (IV-d) is selected from the group consisting of:
3-(4-fluoro-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-dichlorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-dimethoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-(difluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-(difluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(3-(methylsulfonyl)phenyl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(3-(methylsulfonyl)phenyl)-3-(4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxyx amides;
3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine -4-carboxamide;
3-(2-fluoro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-(difluoromethoxy)-2-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-fluoro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-methyl-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-(difluoromethoxy)-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-(fluoromethoxy)-2-methylphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine- 4-carboxamide;
3-(3,4-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)-3-(3,4,5-trifluorophenoxy)pyridazine-4-carboxamide;
3-(2,5-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,3-difluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-3-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(3-fluoro-4-(trifluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-(difluoromethoxy)-3-fluorophenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(3-fluoro-4-(fluoromethoxy)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(4-chloro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and
3-(2-(dimethylamino)phenoxy)-N-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide. 172. The compound of claim 171, which is a compound of formula (IV-e).

here:
R ₃ is -CF ₂ H, -CH ₂ F, halogen, -OCF ₃ , -OCHF ₂ , -OCFH ₂ , cyclopropyl, branched or straight chain C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxyl, cyanopropyl selected from the group consisting of no, nitro, -SCF ₃ , and SF ₅ ;
R ₄ is selected from the group consisting of H and branched or straight chain C ₁ -C ₄ alkyl. 186. The compound of claim 185, wherein the compound of formula (IV-e) is selected from the group consisting of:
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(difluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(fluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-chloro-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(trifluoromethoxy)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(difluoromethoxy)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(fluoromethoxy)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-bromo-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-cyclopropyl-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-tert-butyl-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-isopropyl-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-methyl-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5,6-dimethyl-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-methoxy-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-5-methyl-6-methoxy-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-cyano-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-nitro-pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-((trifluoromethyl)thio)pyridazine-4-carboxamide ; and
3-(2-chloro-4-fluorophenoxy)-N-(3-(S-methylsulfonimidoyl)phenyl)-6-(pentafluoro-λ ⁶ -sulfanyl)pyridazine-4-car Voxamide. 172. The compound of claim 171, which is a compound of formula (IV-f).

here:
R ₁ is ego; here
R _1a , R _1b , R _1c , R _1d , and R _1e are each independently H, C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxyl, -OCF ₃ , -OCHF ₂ , -OCH ₂ F , -OCH ₂ CF ₃ , and -NR ₅ R ₆ , where R ₅ and R ₆ are C ₁ -C ₄ alkyl, provided that R _1a , R _1b , R _1c , R _1d , and R At least one of _1e is not H. 188. The compound of claim 187, wherein:
(i) R _4a is halogen; R _2a is selected from the group consisting of H, C ₁ -C ₄ alkyl, halogen, and C ₁ -C ₄ alkoxyl; R _3a is H or halogen; R _5a is H or halogen; R _6a is H;
(ii) R _2a is C ₁ -C ₄ alkoxyl and R _4a is selected from the group consisting of C ₁ -C ₄ alkoxyl and halogen;
(iii) R _4a is -OF ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(iv) R _4a is -OCHF ₂ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(v) R _4a is -OCH ₂ F; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a and R _6a are each H; R _5a is H or halogen;
(vi) R _4a is -OCH ₂ F ₃ ; R _2a is selected from the group consisting of H, halogen and C ₁ -C ₄ alkyl; R _3a , R _5a and R _6a are each H;
(vii) R _3a is halogen; R _2a is H or halogen; R _4a and R _5a are H; R _6a is H or halogen; and
(viii) R ₂ is -NR ₅ R ₆ ; R _3a , R _4a , R _5a , and R _6a are each H. According to clause 187,
R ₁

A compound selected from the group consisting of. 188. The compound of claim 187, wherein the compound of formula (IV-f) is selected from the group consisting of:
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-dichlorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,4-dimethoxyphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide;
3-(2-chloro-4-(difluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide;
3-(2-chloro-4-(fluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-car boxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide hydrochloride ;
3-(4-(difluoromethoxy)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoromethyl)pyridazine -4-carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoro Romethyl)pyridazine-4-carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4 -carboxamide;
3-(4-(difluoromethoxy)-2-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-fluoro-4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4- carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-methyl-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4- carboxamide;
3-(4-(difluoromethoxy)-2-methylphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4- carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-(fluoromethoxy)-2-methylphenoxy)-6-(trifluoromethyl)pyridazine-4-car boxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(2-methyl-4-(2,2,2-trifluoroethoxy)phenoxy)-6-(trifluoro methyl)pyridazine-4-carboxamide;
3-(3,4-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)-3-(3,4,5-trifluorophenoxy)pyridazine-4-carboxamide ;
3-(2,5-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2,3-difluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-chloro-3-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(3-fluoro-4-(trifluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4 -Carboxamide;
3-(4-(difluoromethoxy)-3-fluorophenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4 -Carboxamide;
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(3-fluoro-4-(fluoromethoxy)phenoxy)-6-(trifluoromethyl)pyridazine-4- carboxamide;
3-(4-chloro-2-methoxyphenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide;
3-(2-(dimethylamino)phenoxy)-N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-6-(trifluoromethyl)pyridazine-4-carboxamide; and
N-(3-(N,S-dimethylsulfonimidoyl)phenyl)-3-(4-fluoro-2-methoxyphenoxy)-6-(trifluoromethyl)pyridazine-4-carboxamide . 172. The compound of claim 171, which is a compound of formula (IV-g).

here:
R ₁ is selected from the group consisting of 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-difluorophenyl;
R ₂₀ is C ₁ -C ₄ alkyl;
R ₂₁ is H or C ₁ -C ₄ alkyl. Na _v 1.8 sodium ion, comprising administering to a subject _in need thereof a modulating effective amount of a compound of formula (I-VI) of any one of claims 149-191. How to tune in to a channel. A method of inhibiting Na _v 1.8 comprising administering to a subject _in need thereof an inhibitory effective amount of a compound of formula (I-VI) of any one of claims 149-191. A subject in need of treatment and/or reduction of symptoms of a condition, disease or disorder associated with increased Na _v 1.8 activity or expression is administered a therapeutically effective amount of Formula (I-VI) of any one of claims 149-191. A method of treating and/or reducing the symptoms of a condition, disease or disorder associated with increased Na _v 1.8 activity or expression, comprising administering a compound to treat and/or reduce the symptoms of the condition, disease or disorder. 195. The method of claim 194, wherein the condition, disease or disorder associated with increased Na _v 1.8 activity or expression is selected from the group consisting of pain, respiratory disease, neurological disorder and psychiatric disease, and combinations thereof. 195. The method of claim 195, wherein the pain is neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, postoperative pain, labor pain, labor pain, neurogenic bladder, ulcerative colitis, A method selected from the group consisting of chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve damage, and combinations thereof. 194. The method of claim 194, wherein the disease or condition is HIV-treatment induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis. ALS, diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenia gravis syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism. , bipolar depression, anxiety, schizophrenia, diseases related to sodium channel toxicity, familial erythrodynia, primary erythrodynia, familial proctalgia, cancer, epilepsy, partial and generalized tonic seizures, restless legs syndrome, arrhythmia, fibromyalgia, A method selected from the group consisting of neuroprotection under ischemic conditions induced by stroke or neurological trauma, tach-arrhythmias, atrial fibrillation, ventricular fibrillation and Pitt Hopkins syndrome (PTHS). 195. The method of claim 194, further comprising administering to the subject one or more additional therapeutic agents. 199. The method of claim 198, wherein the one or more additional therapeutic agents are selected from the group consisting of acetaminophen, one or more NSAIDs, opioid analgesics, and combinations thereof. Formula (I-IV) of any one of claims 149 to 191 in the manufacture of a medicament for the treatment of a condition, disease or disorder associated with increased Na _v 1.8 activity or expression in a subject suffering from such disorder. Uses of Compounds. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

here:
R ₁ is an optionally substituted 5 or 6 ring-membered ring comprising -CN, -CF ₃ , an aryl or heteroaryl ring, wherein the 5 or 6 ring-membered ring optionally contains one or more N or S in the ring; , Substitution on the 5 or 6 ring member ring is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring has 5 or is selected from fused heterocyclyl with 6 members, heteroaryl with 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;
R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;
R ₃ is halogen, alkyl or alkoxy;
R ₄ is halogen, alkyl or H;
R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring having 5 or 6 members. a fused heterocyclyl, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;
X is CH or N;
Z is CH or N,
where X and Z are not both CH;
R ₂ is -CH ₃ , -CD ₃ , or -CT ₃ where D is deuterium and T is tritium;
R ₃ is -CH ₃ , -CD ₃ , or -CT ₃ where D is deuterium and T is tritium. A compound of formula (IV) or a pharmaceutically acceptable salt thereof.

here:
Y is N or CR ₁₃ ;
A and B are independently aryl, heteroaryl, or a 3-6 membered ring containing one or more heteroatoms independently selected from O, S, and N; where A is unsubstituted or:
H, halo, C1-C6-alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, SR', -CH ₂ -cycloalkyl, -CF ₂ - Cycloalkyl, -CH(CH ₃ )-cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH(-CH ₃ )-aryl, C(=O)-alkyl, -C(=O)cyclo Alkyl, -C(=O)-NH-alkyl, -C(=O)NH ₂ , hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, NR'R"-NHSOR', -NHC(=O)-alkyl -NH(C=O)NR'R", SO ₂ R', trifluoromethyl, bromo, chloro, fluoro, cyclopropylmethyl, sulfonylmethyl, 3-6 membered cycloalkyl; is substituted with one or more substituents selected from 3-6 membered heterocycloalkyl, any of which may have one or more substituents, wherein the 3-6 membered heterocycloalkyl is independently selected from O, S, and N. contains at least one heteroatom;
R ₁₂ , R ₁₃ and R ₁₄ are individually selected from H, CF ₃ , halo, C1-C6-alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH ₂ -cycloalkyl, -CF ₂ -cycloalkyl, -CH(CH ₃ )-cycloalkyl, -CH ₂ -aryl, -CF ₂ -aryl, -CH(-CH ₃ )-aryl, C(=O )-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH ₂ , hydroxy, -COOH (and esters thereof), alkylsulfonyl, aryl sulphenyl Ponyl, sulfonamide, amino, NR'R" -NHSO ₂ R1, -NHC(=O)-alkyl -NH(C=O)NR'R", spirocyclyl, morpholinyl, pyrrolidinyl, piperidi selected from nyl, carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein the 5 or 6 ring member ring optionally contains one or more N or S within the ring, and wherein substitution on the 5 or 6 ring member ring Silver halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, -C(=O)-NH-alkyl, -C(=O)NH ₂ cyano, CF ₃ , CHF ₂ , OCH ₃ , OCF ₃ , fused heterocyclyl with each ring having 5 or 6 members, heteroaryl with 5 or 6 ring members, saturated heterocyclyl or partially unsaturated heterocyclyl. and each of these is optionally substituted if valency permits;
Substituents R' and R" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. , or from CD ₃ can be selected 203. The compound of claim 202, wherein A is CH ₂ CF ₃ . Clause 202, wherein A Phosphorus compounds. Compounds of formula (V).

here
A and B are as described in formula (IV);
R ₂ is as described in formula (II);
R ₁₃ and R ₁₄ are as described in formula (IV);
X is CH or N;
Y is NR ₈ or O;
Z is CH, N or NO. A compound of formula (I) or a pharmaceutically acceptable salt thereof.

here:
R ₁ is an optionally substituted 5 or 6 ring-membered ring comprising -CN, -CF ₃ , an aryl or heteroaryl ring, wherein the 5 or 6 ring-membered ring optionally contains one or more N or S in the ring; , Substitution on the 5 or 6 ring member ring is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring has 5 or is selected from fused heterocyclyl with 6 members, heteroaryl with 5 or 6 ring members, saturated heterocyclyl, or partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;
R ₂ is alkyl, haloalkyl, alkoxy or haloalkoxy;
R ₃ is halogen, alkyl or alkoxy;
R ₄ is halogen, alkyl or H;
R ₅ is H, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkyl sulfonyl, alkyl sulfoxyminyl, alkyl sulfonamide, cyano, CF ₃ , OCF ₃ , each ring having 5 or 6 members. a fused heterocyclyl, a heteroaryl having 5 or 6 ring members, a saturated heterocyclyl, or a partially unsaturated heterocyclyl, each of which is optionally substituted as valence permits;
X is CH or N;
Z is CH or N,
However, both X and Z cannot be CH. 207. The compound of claim 206, wherein R ₂ is selected from the group consisting of -CH ₃ , -CD ₃ or -CT ₃ , wherein D is deuterium and T is tritium. 206. The method of claim 206, wherein R ₃ A compound selected from the group consisting of -CH ₃ , -CD ₃ or -CT ₃ , wherein D is deuterium and T is tritium. 207. The compound of claim 206, wherein R ₅ is optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, or halogen. Examples 7 - Compounds selected from the compounds mentioned in 101. A compound selected from the compounds mentioned in Examples 103-105. A compound selected from the compounds mentioned in Examples 110-114. A compound selected from the compounds mentioned in Example 119. A compound selected from the compounds mentioned in Example 121.

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